Antiviral agents. I. Synthesis and antiviral evaluation of trimeric naphthoquinone analogues of conocurvone

Article abstract of DOI:10.1071/CH08177

Conocurvone, a novel natural product isolated from the endemic Australian shrub Conosperum sp. (Proteaceae), exhibits anti-HIV activity but is a highly lipophilic compound, which suggests that there may be problems with its aqueous solubility and bioavailability. A general and convenient synthesis of trimeric naphthoquinones using the condensation of 2-hydroxynaphthoquinones and 2,3-dihaloquinones is described. The application of this method to the synthesis of a series of simpler and less lipophilic trimeric naphthoquinone simple analogues of conocurvone is also reported together with their anti-HIV activity. CSIRO 2008.

Full text of DOI:10.1071/CH08177

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 768–784
www.publish.csiro.au/journals/ajc
Antiviral Agents. I. Synthesis and Antiviral Evaluation of
Trimeric Naphthoquinone Analogues of Conocurvone
Ian T. Crosby,A,H Mark L. Rose,A,C Maree P. Collis,B,D Paula J. de Bruyn,A,E
Philip L. C. Keep,B,F and Alan D. RobertsonB,G
AMedicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,
Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC 3052, Australia.
BAMRAD Operations Pty Ltd, 576 Swan Street, Richmond, VIC 3121, Australia.
CPresent address: PROBE Analytical, 1/19-23 Paramount Road, West Footscray,
VIC 3012, Australia.
DPresent address: Lethbridge Wines, 74 Burrows Road, Lethbridge, VIC 3332, Australia.
EPresent address: DaviesCollisonCave, 1 Nicholson Street, Melbourne, VIC 3000, Australia.
FPresent address: CSL, 45 Poplar Road, Parkville, VIC 3052, Australia.
GPresent address: Pharmaxis Ltd, 2/10 Rodborough Road, Frenchs Forest, NSW 2086, Australia.
HCorresponding author. Email: ian.crosby@vcp.monash.edu.au
Conocurvone, a novel natural product isolated from the endemic Australian shrub Conosperum sp. (Proteaceae), exhibits
anti-HIV activity but is a highly lipophilic compound, which suggests that there may be problems with its aqueous
solubility and bioavailability. A general and convenient synthesis of trimeric naphthoquinones using the condensation
of 2-hydroxynaphthoquinones and 2,3-dihaloquinones is described. The application of this method to the synthesis of a
series of simpler and less lipophilic trimeric naphthoquinone simple analogues of conocurvone is also reported together
with their anti-HIV activity.
Manuscript received: 28 April 2008.
Final version: 15 July 2008.
Introduction
that there may be problems with their aqueous solubility and
bioavailability.
Conocurvone 1 was isolated from the endemic Australian
shrub Conosperum sp. (Proteaceae) by the National Cancer
Institute (USA) using anti-HIV bioassayed fractionation of
organic extracts.[1] The nature of this intriguing trimeric naph-
thoquinone structure led us to believe that its mode of HIV
inhibition was unlikely to be the clinically used reverse tran-
scriptase or protease inhibition. Indeed conocurvone has been
shown to be an inhibitor of both HIV integrase and HIV-
mediated cell fusion.[2,3] Conocurvone and the semi-synthetic
trimeric analogue 2 (Fig. 1) were both active and equipo-
tent yet both were highly lipophilic and it suggested to us
The equipotency of conocurvone 1 and its analogue 2 sug-
gested that less complex compounds, such as 3 (Fig. 2), may
still retain significant anti-HIV activity. Compounds based on 3
are less lipophilic than 1 or 2, and have the additional advan-
tage of being less stereochemically complex. Here we report the
synthesis and anti-HIV activity of 3 and a series of analogues.
Results and Discussion
The National Cancer Institute (NCI) reported the synthesis of
2 from 1,4-naphthoquinone 4 and teretifolione B 5 by reaction
O
O
HO
O
HO
O
O
O
O
O
O
O
O
O
O
O
O
HO
O
HO
O
1
2
Fig. 1. Conocurvone 1 and the semi-synthetic trimeric analogue 2.
© CSIRO 2008 10.1071/CH08177
0004-9425/08/100768

Naphthoquinone Analogues of Conocurvone
769
in either acetic acid or pyridine in 9 and 8% yield respectively
(Scheme 1).[1]
We reasoned that the same trimeric naphthoquinone nucleus
could be more efficiently synthesized by use of 2,3-dihalo-1,4-
naphthoquinone, as had been used in the reaction with silyl
enol ethers.[4] Accordingly, reaction of teretifolione B[5] 5 with
2,3-dibromo-1,4-naphthoquinone[6] 6a in the presence of diiso-
propylethylamine in tetrahydrofuran resulted in the formation
of the ‘dimeric’ naphthoquinone 7a in 48% yield. Alterna-
tively, the reaction of teretifolione B[5] 5 with 2,3-dichloro-1,4-
naphthoquinone 6b in the presence of diisopropylethylamine
in 1,2-dimethoxyethane gave 7b (60% yield). Others have also
synthesized 7b by reacting 5 and 6b in the presence of cae-
sium carbonate in acetonitrile over 7 days.[7] Further reaction
under essentially the same conditions of 7a with 5 afforded the
known ‘trimer’2 in 22% yield after purification by size exclusion
chromatographyThe spectroscopic data for 2 was in good agree-
ment with that previously reported and displayed similar isomer
resonances attributed to tautomerism and/or restricted rotation
about one or more bonds in the molecule.[1] With the successful
synthesis of 2, albeit in a modest yield, attention was then turned
to the stereochemically simpler 3 (Scheme 2).
O
HO
O
O
O
O
O
O
HO
O
Reaction of 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione[5] 8 with 2,3-dibromo-1,4-naphthoquinone[6]
6a in the presence of diisopropylethylamine in tetrahydrofuran
3
Fig. 2. The less complex Conocurvone analogue 3.
O
O
HO
O
O
O
O
O
AcOH
or
HO
O
O
O
O
pyridine
O
O
HO
4
5
2
Scheme 1.
O
O
O
O
O
HO
O
iPr2NEt
X
X
HO
O
O
6a THF, ∆
6b DME, RT
O
X
6a X ϭ Br
6b X ϭ Cl
5
7a X ϭ Br
7b X ϭ Cl
O
iPr2NEt/THF 7a
5
O
HO
O
O
O
O
O
HO
O
O
2
Scheme 2.

770
I. T. Crosby et al.
gave the ‘dimer’ 9a in 68% yield. Further reaction of 8 with
9a under essentially the same conditions gave the ‘trimer’ 3 in
80% yield after purification by size exclusion chromatography
(Scheme 3). Reaction of 5 with 7a in the presence of diiso-
propylethylamine in tetrahydrofuran afforded the asymmetrical
‘trimer’ 10 in 15% yield after purification by size exclusion
chromatography. Alternatively, reaction of 8 with 6b in the
presence of diisopropylethylamine in 1,2-dimethoxyethane at
room temperature gave 7b, which reacted with additional 8
at reflux to give the same asymmetrical ‘trimer’ 10 in 48%
yield after flash chromatography. This demonstrates the ability
of this methodology to access complex asymmetrical trimeric
naphthoquinones.
The physicochemical properties of the trimeric naphtho-
quinones make them sometimes difficult to purify by con-
ventional methods, and size exclusion chromatography could
be used to separate monomeric, dimeric, and trimeric species
but only on a small scale due to solubility issues. Alterna-
tively, diacetylation of 3 afforded the diacetate 11 that could be
chromatographed on silica with deacetylation being achieved
using aluminium trichloride in dichloromethane (Scheme 4).
Also isolated from the acetylation was a rearranged material
12, whose structure was determined by single crystal X-ray
crystallography (D. Hockless, unpubl. data). Its formation is
rationalized below (Scheme 4) and involves a rearrangement
of the β,γ-ene-α,δ-dione 13, in a vinylous benzylic acid-type
rearrangement[8] catalyzed by pyridine.
carefully adding water, and collecting the microprisms by fil-
tration. Preparative HPLC was used to provide 3 in >99%
purity. Biological evaluation was undertaken at Fairfield Hos-
pital (Victoria, Australia) against HIV-1 Rf CEM-SS (human
lymphoblastoid cells) cells (Table 1).
With the anti-HIV activity of the stereochemically simpler
naphthoquinone trimer 3 established, the synthesis of a series
of analogues was undertaken. Hydrogenation of 8 using Adam’s
catalyst followed by aerial oxidation gave 14. Compound 14
wassubsequentlyreactedwith2,3-dichloro-1,4-naphthoquinone
6b, acetylated to 15, purified and deacetylated to afford 16
(Scheme 5).
Reaction of 3 with N,N-dimethylcarbamyl chloride in pyri-
dine under reflux gave the biscarbamate 17 in 58% yield
(Scheme 6).
Biological evaluation was undertaken at Fairfield Hospital
against HIV-1 Rf CEM-SS cells of the derivatives of the pendant
quinone moieties 11, 15, and 17 and is shown in Table 2.
The diacetate 11 was slightly more active than its parent 3,
which probably indicates that it acts as a prodrug of 3, being
hydrolyzed by cellular esterases, with its slightly greater activity
perhaps reflecting better transport across cellular membranes.
The biscarbamate 17 did not show comparable activity to 3 pos-
sibly as a function of its expected greater hydrolytic stability.The
tetrahydro derivative 15 displayed a different inhibition profile,
perhaps confirming the importance of the pyran ring as noted in
the original conocurvone paper.[1]
In general it was found that reactions carried out in 1,2-
dimethoxyethane were cleaner and proceeded more readily than
those carried out in tetrahydrofuran and that reactions using 2,3-
dichloro-1,4-naphthoquinone 6b gave less side products than
2,3-dibromo-1,4-naphthoquinone[6] 6a. For larger scale prepa-
ration of 3, dilution of the reaction mixture of 6b and 8 with
dichloromethane and acidification (1 M aqueous hydrochloric
acid) allowed for the convenient isolation of the product by fil-
tration (50% yield). The product could be purified by boiling
in acetic acid, filtration, and subsequent washing of the product
with hot acetic acid and hot ethanol. Alternatively, the product
could be purified by dissolving in hot N,N-dimethylformamide,
Attention was then directed to substitution on the central
quinone of a simpler conocurvone analogue 3. A variety of 2,3-
dichloro-6-alkoxy-1,4-naphthoquinones were synthesized from
2,3-dichloro-6-hydroxy-1,4-naphthoquinone[9] 18, synthesized
from trichloro-1,4-benzoquinone 19 and trans-1-methoxy-3-
trimethylsilyloxybuta-1,3-diene[10] 20. Alkylation of the pheno-
lic hydroxy group was achieved by treatment with an appropriate
alkyl halide in the presence of silver(i) oxide to afford the
methyl ether 21, the propyl ether 22, and the pentyl ether 23
(Scheme 7).
Reactions of these naphthoquinone ethers 21–23 with 8 were
carried out and the yields are unoptimized. Reaction of the
O
O
O
HO
O
HO
O
iPr2NEt
THF
X
X
O
O
O
O
X
6a X ϭ Br
6b X ϭ Cl
8
9a X ϭ Br
9b X ϭ Cl
O
5
iPr2NEt/THF
iPr2NEt/THF
7b ϩ 8
8
iPr2NEt
DME
O
O
O
HO
O
HO
O
O
O
O
O
O
O
O
O
HO
O
HO
O
O
10
3
Scheme 3.

Naphthoquinone Analogues of Conocurvone
771
Me
Me
Me
Me
Me
O
O
Me
O
O
O
O
pyϩ
O
H
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
OAc
AcO
OAc
AcO
O
O
O
HO
Me
Me
Me
Me
Me
Me
O
13
Ac2O, py
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
AcO
O
O
O
O
ϩpy
O
H
O
O
O
O
O
O
O
O
O
OAc
AcO
OAc
O
O
AcO
O
AcO
Me
Me
Me
Me
O
Me
Me
11
12
Scheme 4.
Table 1. Viral cytopathic (cpe) effect against HIV-Rf CEM-SS cells
R
O
HO
O
O
O
O
O
O
HO
O
RЈ
Max. NT, maximum non-toxic dose; SI, selectivity index
Compound
R
Rꢀ
IC50
Max. NT [µM]
SI
[nM]
1
2
10
3
Conocurvone
27
27
8.5
29
50
10
1
1852
370
118
345
CH2CH2CH=CMe2
CH2CH2CH=CMe2
CH2CH2CH=CMe2
Me
Me
Me
10
methylether 21with 8gavethemethoxytrimer 24, afterpurifica-
tion via the diacetate, in 11% yield. Reaction of the propyl ether
22 with 8 gave the propyloxy trimer 25 in 18% yield. Reaction
of the pentyl ether 23 with 8 gave the pentyloxy trimer 26 in
41% yield (Scheme 8).
Reaction of p-chloranil 27 with trans-1-methoxy-3-
trimethylsilyloxybuta-1,3-diene[10] 20 gave 2,3,5-trichloro-6-
hydroxy-1,4-naphthoquinone[9] 28 in 68% yield, which was
methylated under standard conditions to give 2,3,5-trichloro-
6-methoxy-1,4-naphthoquinone[9] 29 in 94% yield. Reaction of
29 with 8 followed by acetylation gave the diacetate 30 in 20%
yield after purification. Deacetylation of the diacetate 30 with
aluminium trichloride proceeded smoothly to afford the chloro
methoxy trimer 31 in 92% yield (Scheme 9).
Attempts were made to improve the physicochemical
properties of the trimeric naphthoquinones by isosteric replace-
ment of carbons of the central quinone by nitrogen. 8-
Hydroxyquinoline 32 was reacted with nitrous acid to give
8-hydroxy-5-nitrosoquinoline hydrochloride 33 in 88% yield,
which was then reduced by sodium dithionite to afford

772
I. T. Crosby et al.
O
O
O
O
O
O
HO
O
Cl
Cl
HO
O
(1) H2, PtO2
(2) Air
ϩ
8
14
6b
(1) iPr2NEt, DME
(2) Ac2O, py
O
O
O
AcO
HO
O
O
O
O
O
O
AlCl3, CH2Cl2
O
O
O
O
O
HO
O
O
AcO
16
15
Scheme 5.
O
O
Me2NCOO
O
HO
O
O
O
Me2NCOCl, py
O
O
O
O
O
O
O
HO
O
O
Me2NCOO
O
3
17
Scheme 6.
5-amino-8-hydroxyquinoline 34 in 83% yield.[11] Oxidative
bromination of 34 was achieved in 43% yield by treatment
with sodium bromate to afford 6,7-dibromoquinoline-5,8-dione
35.[12] It is worth noting that the electrospray ionization (ESI)
mass spectrum of 35 showed apparent ions of reduction, whereas
the electron impact mass spectrum did not. Reaction of 35 with
8 followed by acetylation gave the 5-aza analogue diacetate 36 in
22% yield. Normal aluminium trichloride deacetylation proved
fruitless; however, successful deacetylation was achieved by
treatment in lithium hydroxide in aqueous tetrahydrofuran. This
gave what appeared to be the 5-aza trimeric naphthoquinone
37, which proved to be too unstable to characterize satisfacto-
rily (Scheme 10). The diacetate 36 was assayed as effectively a
prodrug of 37, as 11 acts as a prodrug of 3.
Synthesis of the isoquinoline analogue (Scheme 11) com-
menced with Fremy’s salt oxidation of 5-hydroxyisoquinoline
38 that afforded isoquinoline-5,10-dione[13] 39 in 45% yield.
Sodium dithionite reduction of 39 followed by oxidative bromi-
nation using sodium bromate gave 2,3-dibromoisoquinoline-
5,10-dione 40 in 12% overall yield. It is again worth noting that
the ESI mass spectrum of 40 showed apparent ions of reduction,
whereas the electron impact mass spectrum did not. Reaction of
40 with 8 followed by acetylation gave the 6-aza analogue di-
acetate 41. Treatment of the diacetate 41 with lithium hydroxide
in aqueous tetrahydrofuran, as had been done for the conver-
sion of 36 to 37, proved unsuccessful. The diacetate 41 was
assayed as effectively a prodrug of 42, as 11 acts as a prodrug
of 3.
Biological evaluation was undertaken at Fairfield Hospital
against HIV-1 Rf CEM-SS cells of the derivatives of the central
quinone moiety, and is shown in Table 3.
For several reasons compound 3 was chosen for evalua-
tion in vivo. Toxicity studies of compound 3 in five male and
five female rats with continuous infusion over 2 h of 20 and
40 mg kg−1 administered on days 1, 4, 8, and 11 showed that
the compound was well tolerated with red staining in the cage
noted after 9 days. Toxicity studies of compound 3 in five male
and five female beagles with continuous infusion over 2 h of
25–80 mg kg−1 administered on days 1, 4, 8, and 11 showed that
the compound was fairly well tolerated with t1/2 = 12–72 h and
the compound highly plasma protein bound. Unfortunately com-
pound 3 showed some signs of heptatoxicity in beagles and so
further evaluation in other animal models was not undertaken.
Conclusions
Several less lipophilic and stereochemically simpler conocur-
vonone analogues were synthesized and evaluated for their anti
HIV-1 Rf activity in CEM-SS cells. Compound 3 was also found
to be well tolerated in rats and fairly well tolerated in beagles
with some signs of heptatoxicity observed.
Experimental
General
Melting points were determined on a Reichert Micro-melting
point apparatus and are uncorrected. IR spectra were recorded

Naphthoquinone Analogues of Conocurvone
773
Table 2. Viral cytopathic (cpe) effect against HIV-Rf CEM-SS cells
O
R
R
O
++++, no inhibition (I); +++, minor I; ++, moderate I; +, good I; −, complete I (inhibition of p24 synthesis,
% control); Sl., slightly; ppt, precipitate
Compound
R
Conc. [µM]
0.001
0.01
0.1
1.0
10
20
O
HO
O
O
3
(101.5) +++
+
+/−
Trace
(3.4)
Sl. toxic
(49.7)
(7.3)
(9.8)
O
O
HO
15
(66.2) +++
++
+
+/−
Toxic
(23.6)
(20.9) (14.5) (5.5)
O
O
AcO
O
11
17
+++
+
Trace
Trace
(62.8)
(23.6) (17.0) Sl. toxic (19.2)
O
O
O
Me2NCOO
O
++++
++
+
−
Toxic
ppt
ppt
ppt
OMe
O
O
O
(1)
, CH2Cl2
OSiMe3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
R-X, Ag2O
CH2Cl2
20
(2) HCl/THF
(3) NaOAc/EtOH
OH
OR
O
O
O
21 R ϭ Me
19
18
22 R ϭ (CH2)2CH3
23 R ϭ (CH2)4CH3
Scheme 7.
on a Hitachi 270-30 Infra-Red spectrophotometer as KBr discs
unless indicated otherwise. UV-Vis spectra were recorded as
ethanolic solutions on a Pharmacia Biotech Ultraspec 2000
Chemical shifts for all 13C spectra are reported in parts
per million (ppm), using the solvent chemical shift as the
reference.[14] Fast atom bombardment (FAB) mass spectra were
determined using a JEOL JMS-DX300 mass spectrometer.
The thioglycerol/glycerol matrix was used for samples ana-
lyzed by FAB. ESI mass spectra were determined in positive
ion mode using a Micromass Platform II Mass Spectrometer.
High-resolution mass spectra were determined using a Bruker
BioApex II FTICR Mass Spectrometer. In reporting spectro-
scopic data the following abbreviations have been used: DMSO,
dimethyl sulfoxide; s, singlet; d, doublet; t, triplet; q, quartet;
1
UV-VIS spectrophotometer utilising Swift II software. H and
13C NMR spectra were recorded at 300 MHz and 75.4 MHz,
respectively, using a Bruker Avance DPX 300 spectrometer
equipped with a Silicon Graphics work station. Chemical shifts
for all 1H spectra are reported in parts per million (ppm),
using tetramethylsilane (TMS) as the internal reference. Proton
assignments were based upon coupling constants and two-
dimensional homonuclear (1H/1H) correlation spectroscopy.

774
I. T. Crosby et al.
O
O
HO
O
O
O
O
O
O
O
iPr2NEt
DME
Cl
Cl
HO
O
O
O
OR
RO
8
HO
O
21 R ϭ Me
22 R ϭ (CH2)2CH3
23 R ϭ (CH2)4CH3
24 R ϭ Me
25 R ϭ (CH2)2CH3
26 R ϭ (CH2)4CH3
Scheme 8.
OMe
O
O
O
O
(1)
, CH2Cl2
OSiMe3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
MeI, Ag2O
20
(2) HCl/THF
CH2Cl2
Cl
OH
OMe
O
O
Cl
Cl
29
27
28
O
(1) iPr2NEt, DME
(2) Ac2O, py
HO
O
8
O
O
O
O
HO
O
AcO
O
O
O
O
O
O
O
AlCl3, CH2Cl2
MeO
MeO
Cl
O
Cl
HO
O
O
AcO
O
O
31
30
Scheme 9.
NO
OH
O
NH2
OH
Br
Br
Na2S2O4
NaBrO3
NaNO2, HCl
N
N
N
N
O
OH
34
35
32
33
O
O
(1) iPr2NEt, DME
(2) Ac2O, py
HO
O
8
O
O
HO
O
AcO
O
O
O
O
O
O
O
LiOH, aq. THF
O
O
N
N
O
O
AcO
HO
O
O
37
36
Scheme 10.

Naphthoquinone Analogues of Conocurvone
775
O
O
OH
O
Br
Br
(1) Na2S2O4
(2) NaBrO3
(KSO3)2NO
N
N
N
O
O
40
39
38
O
(1) iPr2NEt, DME
(2) Ac2O, py
HO
8
O
O
O
HO
O
O
AcO
O
O
O
LiOH, aq. THF
O
O
O
O
O
N
N
O
HO
O
O
AcO
O
42
41
Scheme 11.
Table 3. Viral cytopathic (cpe) effect against HIV-Rf CEM-SS cells
O
HO
O
O
O
O
O
O
R
HO
O
++++, no inhibition (I); +++, minor I; ++, moderate I; +, good I; −, complete I (inhibition of p24 synthesis, % control);
Tox, toxic; CC50, 50% cytotoxic conc.
Compound
R
Conc. [µM]
IC50 [µM]
CC50 [µM]
0.01
0.1
1.0
10
20
3
+++
+++
+
+/−
+/−
Trace
Trace
<5% Tox
<5% Tox
20% Tox
0% Tox
Tox
1.33
19
26
27
28
31
36
37
41
6-OMe
++
6-OPrn
0.24
0.43
>20
>20
6-OnPentn
5-Cl, 6-OMe
5-aza(Ac)2
5-aza
++++
+++
+
<5% Tox
Trace
+
+++
+++
+++
+++
++
+
<5% Tox
6-aza(Ac)2
Tox
p, pentet; m, multiplet; br, broad; app, apparent; M, molecular
ion; TG/G, thioglycerol/glycerol; 3NBA, 3-nitrobenzyl alcohol.
Analytical reverse-phase HPLC was performed on a Waters
HPLC system fitted with a Nova-Pak HR C18 column (6 µm,
60 Å, 8 mm × 100 mm) using a binary solvent system; solvent
A: 0.1% TFA/H2O; solvent B: 0.1% TFA/90% CH3CN/H2O.
Analyses were conducted using isocratic (60% A/40% B, flow
rate 1.5 mL min−1, UV detection at 264 nm) and gradient (100%
A to 100% B over 30 min, flow rate 1.5 mL min−1, UV detection
at 264 nm) elution modes unless otherwise stated. TLC was car-
ried out on silica gel 60 F254 pre-coated plates (0.25 mm, Merck,
ART 5554). Preparative TLC was performed on glass plates
(20 cm × 20 cm × 2 mm, Merck, ART 5717). Flash column
chromatography[15] was carried out routinely using Merck Silica
gel 60, 230–400 mesh ASTM. Elemental analyses were carried
outonsamplesdriedundervacuumoverphosphoruspentoxideat
30◦C for 24 h, by Chemical & MicroAnalytical Services Pty Ltd,
Melbourne, or Microanalytical Service, Chemistry Department,
University of Queensland, Brisbane, Queensland. All solvents
used were redistilled before use. Tetrahydrofuran was distilled
from sodium metal/benzophenone ketyl under nitrogen immedi-
ately before use. Dry dichloromethane and 1,2-dichloroethane
were obtained by distillation from phosphorus pentoxide fol-
lowed by storage over 3 Å molecular sieves. Dry ethanol

776
I. T. Crosby et al.
and methanol were distilled from their respective magnesium
alkoxides and stored over type 4 Å and 3 Å molecular sieves,
respectively.
Stirring was maintained for 1 h, after which the solu-
tion was poured into ice-cold aqueous hydrochloric acid
(1 M, 200 mL) and extracted with ether. The extracts
were washed with saturated brine, dried, and evaporated.
The residue was dissolved in acetonitrile (150 mL), N,Nꢀ-
bis(salicylidene)ethylenediaminocobalt(ii) hydrate (0.50 g)
added and oxygen bubbled through the mixture overnight.Addi-
tional N,Nꢀ-bis(salicylidene)ethylenediaminocobalt(ii) hydrate
(250 mg) was added and the bubbling of oxygen continued
for 8 h after which further N,Nꢀ-bis(salicylidene) ethylene-
diaminocobalt(ii) hydrate (250 mg) was added and the bubbling
of oxygen continued overnight. The volatiles were removed and
the residue subjected to flash chromatography in 20% ethyl
acetate in hexane. The major fraction gave ( )-3-methyl-3-
(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-9,10-dione as
a purple oil (8.97 g, 76%). δH 1.39 (3H, s, 3-CH3), 1.52, 1.61
(3H, 3H, br s, br s, 4ꢀ-CH3, H5ꢀ), 1.64–1.81 (2H, m, H1ꢀ), 2.05
(2H, distorted q, H2ꢀ), 5.03 (1H, distorted t, H3ꢀ), 5.93 (1H, d, J
10.5, H2), 6.21 (1H, d, J 10, H8), 6.92 (1H, d, J 8, H5), 7.05 (1H,
d, J 8, H6), 7.28 (1H, d, J 10, H7), 7.72 (1H, d, J 10.5, H1). δC
17.6 (3-CH3), 22.6 (C1ꢀ), 25.6, 26.5 (4ꢀ-CH3, C5ꢀ), 41.3 (C2ꢀ),
79.3 (C3), 120.2 (CH), 122.0 (CH), 123.5 (CH), 124.3 (CH),
125.3 (Cq), 125.9 (Cq), 128.5 (Cq), 131.7 (CH), 132.1 (Cq),
136.3 (CH), 147.0 (CH), 156.7 (Cq), 180.8 (Cq), 181.8 (Cq).
m/z (FAB, 3NBA/MeOH) 310 (M + H + 1, 25%), 309 (M + H,
41), 227 (100), 226 (57), 225 (25), 197 (33).
2,3-Dibromo-1,4-naphthoquinone[6]
6
A solution of bromine (1.10 g) in dichloromethane (5 mL) was
added to a stirred solution of 1,4-naphthoquinone 4 (1.00 g) in
dichloromethane(10 mL)andafterstirringfor5 minthevolatiles
were removed under vacuum. Immediately the residue solid-
ified, a solution of sodium acetate (0.56 g) in ethanol (5 mL)
was added. The resulting mixture was heated on a steambath,
boiled for 5 min and allowed to cool to afford 2-bromo-1,4-
naphthoquinone(1.02 g, 68%)asyellowneedles, mp131–132◦C
(lit.[16] 129–130◦C).
A solution of bromine (142 mg) in dichloromethane (1 mL)
was added to a stirred solution of 2-bromo-1,4-naphthoquinone
(200 mg) in dichloromethane (1 mL). After stirring for 40 min
the volatiles were removed under vacuum and a solution of
sodium acetate (73 mg) in ethanol (2 mL) added. The result-
ing mixture was heated on a steambath, boiled for 10 min
and allowed to cool to ambient temperature. The solvent was
removed and the residue passed down a short column of sil-
ica in ethyl acetate to afford 2,3-dibromo-1,4-naphthoquinone
6a (235.2 mg, 88%) as yellow needles from ethyl acetate, mp
219–221◦C (lit.[6] 217–218◦C).
A solution of the foregoing compound (0.96 g) in toluene
(40 mL) was washed twice with a solution of sodium dithio-
nite (5.0 g) in water (50 mL). The resulting pale yellow solution
was then added to a solution of potassium (1.65 g) dissolved
in t-butanol (40 mL) saturated with oxygen. Stirring at ambi-
ent temperature was maintained for 5 min after which methanol
(40 mL) and ice-water (50 mL) were added. The resulting mix-
ture was stirred, acidified with aqueous hydrochloric acid (1 M),
diluted with ether, and the layers separated. The organic phase
was washed with water and extracted with aqueous potassium
carbonate (5%). The alkaline extracts were acidified with aque-
ous hydrochloric acid, extracted with ether, the ether extracts
dried, and evaporated. The resulting residue was subjected
to flash chromatography in ethyl acetate/acetic acid/hexane
(24/1/75) to afford ( )-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-
3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-7,10-dione 5 as an orange oil
(437 mg, 43%), which slowly solidified under vacuum, mp 96–
98◦C (lit.[5] 96–98◦C). δH 1.41 (3H, s, 3-CH3), 1.53, 1.62 (3H,
3H, br s, br s, 4ꢀ-CH3, H5ꢀ), 1.64–1.79 (2H, m, H1ꢀ), 2.07 (2H,
distorted q, H2ꢀ), 5.03 (1H, br t, J 7, H3ꢀ), 5.92 (1H, d, J 10.5,
H2), 6.22 (1H, s, H8), 7.06 (1H, d, J 8.5, H5), 7.57 (1H, br s,
OH), 7.79 (1H, d, J 10.5, H1), 7.92 (1H, d, J 8.5, H6). δC 17.6 (3-
CH3), 22.6 (C1ꢀ), 25.6, 26.6 (4ꢀ-CH3, C5ꢀ), 41.3 (C2ꢀ), 79.4 (C3),
109.1 (CH), 120.0 (CH), 121.6 (Cq), 122.2 (CH), 123.5 (CH),
127.0 (Cq), 128.7 (CH), 132.2 (Cq), 135.5 (CH), 156.5 (Cq),
158.2 (Cq), 184.0 (Cq), 184.4 (Cq). m/z (FAB, 3NBA/MeOH)
326 (M + H + 1, 31%), 325 (M + H, 85), 243 (61), 242 (71),
241 (100), 213 (34).
( )-9-Hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-
3H-naphtho[2,1-b]pyran-7,10-dione ( -Teretifolione B)[5] 5
Amixtureof2,7-dihydroxynaphthalene(16.0 g), citral(17.0 mL),
and pyridine (8.0 mL) was heated at 120◦C for 21 h. The mixture
was cooled, diluted with ether (100 mL), and washed suc-
cessively with sulfuric acid (10%, 100 mL), water (100 mL),
aqueous sodium hydrogen carbonate (2 × 50 mL), and water
(50 mL). The organic phase was dried, evaporated, and the
residue subjected to flash chromatography in 10% ethyl acetate
in hexane followed by 20% ethyl acetate in hexane. The major
fraction afforded ( )-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-
naphtho[2,1-b]pyran-9-ol (24.26 g, 83%) as a brown oil. δH 1.46
(3H, s, 3-CH3), 1.60, 1.69 (3H, 3H, br s, br s, 4ꢀ-CH3, H5ꢀ), 1.73–
1.81 (2H, m, H1ꢀ), 2.18 (2H, distorted q, H2ꢀ), 5.13 (1H, distorted
t, H3ꢀ), 5.60 (1H, d, J 10, H2), 6.44 (1H, br s, OH), 6.85 (1H, d,
J 10, H1), 6.92 (1H, d, J 9, H5), 6.97 (1H, dd, J 9, 2.5, H8), 7.27
(1H, d, J 2.5, H9), 7.56, 7.62 (1H, 1H, d, d, J 9, H6, H7).
The crude foregoing compound (13.57 g) was dissolved
in acetic anhydride (10 mL) and pyridine (20 mL) and the
solution stirred for 2 h. The volatiles were removed under
vacuum, the residue dissolved in ethyl acetate, washed with
aqueous hydrochloric acid (2 × 100 mL), dried, and the sol-
vent removed. The residue was subjected to flash chromato-
graphy in hexane followed by 2% ethyl acetate in hexane.
The major fraction (12.91 g, 83%) was recrystallized from
hexane to afford ( )-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-
naphtho[2,1-b]pyran-9-yl acetate as colourless needles, mp 52–
53◦C (lit.[17] 52–53◦C). δH (90 MHz) 1.43 (1H, s, 3-CH3), 1.56,
1.65 (3H, 3H, br s, br s, 4ꢀ-CH3, H5ꢀ), 1.70–1.83 (2H, m, H1ꢀ),
2.27 (2H, distorted q, H2ꢀ), 2.32 (3H, s, OAc), 5.10 (1H, dis-
torted t, H3ꢀ), 5.63 (1H, d, J 10, H2), 6.85–7.10 (3H, m, H1, H5,
H8), 7.54–7.75 (3H, m, H9, H6, H7).
( )-8-(3ꢀ-Bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-
2ꢀ-yl)-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-
3H-naphtho[2,1-b]pyran-7,10-dione 7a
A
solution of ( )-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-
A
solution of 3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-
naphtho[2,1-b]pyran-9-yl acetate (12.91 g) in dry methanol
(20 mL) was added to stirred solution of sodium
(1.74 g) dissolved in dry methanol (80 mL) under nitrogen.
3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-7,10-dione
5
(127.7 mg),
2,3-dibromo-1,4-naphthoquinone[6] 6a (152 mg), and diiso-
propylethylamine (90 µL) in tetrahydrofuran (10 mL) was
heated under reflux overnight. The volatiles were removed
a

Naphthoquinone Analogues of Conocurvone
777
under vacuum and the residue subjected to flash chromato-
graphy in ethyl acetate/acetic acid/hexane (24/1/75) to
afford ( )-8-(3ꢀ-bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-
yl)-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho
[2,1-b]pyran-7,10-dione 7a as an orange solid (105 mg, 48%).
δH 1.46 (3H, s, 3-CH3), 1.57, 1.66 (3H, 3H, br s, br s, 4ꢀ-CH3,
H5ꢀ), 1.71–1.86 (2H, m, H1ꢀ), 2.12 (2H, distorted q, H2ꢀ), 5.09
(1H, m, H3ꢀ), 5.99 (1H, d, J 10.5, H2), 7.13 (1H, d, J 8.5, H5),
7.75–7.78 (2H, m, H6ꢀ, H7ꢀ), 7.84 (1H, d, J 10.5, H1), 7.90 (1H,
br s, OH), 8.02 (1H, d, J 8.5, H6), 8.12, 8.20 (1H, 1H, m, m,
H5ꢀ, H8ꢀ). m/z (FAB, 3NBA/MeOH) 561 (M[81Br] + H, 12%),
559 (M[79Br] + H, 11), 481 (14), 480 (16), 479 (14), 477 (25),
475 (19), 398 (30), 397 (100), 396 (30).
1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-9-
hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]
pyran-7,10-dione 2 as an orange solid (14.2 mg, 22%), mp
140–150◦C.
Method B
Diisopropylethylamine (270 µL, 1.55 mmol) was added to a
solution of ( )-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-
3H-naphtho[2,1-b]pyran-7,10-dione 5 (103 mg, 0.32 mmol) and
2,3-dichloro-1,4-naphthoquinone 6b (70 mg, 0.31 mmol) in 1,2-
dimethoxyethane (5 mL). The resultant solution was stirred
at room temperature overnight. An aliquot (2 mL) of the
reaction mixture was added to aqueous hydrochloric acid
(1 M) and extracted with ethyl acetate, the extract was dried
and the solvent evaporated to afford a red glassy solid
of ( )-8-(3ꢀ-bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-
9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-
b]pyran-7,10-dione 7b (62 mg, 39%), mp 89–94◦C.
( )-8-(3ꢀ-Chloro-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-
2ꢀ-yl)-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-
3H-naphtho[2,1-b]pyran-7,10-dione 7b
Diisopropylethylamine (1.3 mL, 7.46 mmol) was added to a
solution of ( )-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-
3H-naphtho[2,1-b]pyran-7,10-dione 5 (500 mg, 1.54 mmol)
and 2,3-dichloro-1,4-naphthoquinone 6b (350 mg, 1.54 mmol)
in 1,2-dimethoxyethane (25 mL). The resultant solution
was stirred at room temperature overnight. The reaction
mixture was added to aqueous hydrochloric acid (1 M,
50 mL) and extracted with ethyl acetate (3 × 50 mL), the
extract was dried and the solvent evaporated. The result-
ing residue was subjected to flash chromatography to
afford ( )-8-(3ꢀ-chloro-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-
yl)-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho
[2,1-b]pyran-7,10-dione 7b (480 mg, 60%) as a glassy red solid,
mp 89–94◦C. (Found: C 70.1, H 4.6. C30H23ClO6 requires
C 70.0, H 4.5%.) λmax/nm (ε/M−1 cm−1) 274 (25 700), 295sh
(16 980), 383 (10 230). νmax/cm−1 3448w, 1690m, 1678m,
1642m, 1356m, 1302s, 1274s. δH 1.47 (3H, s, 3-CH3), 1.58,
1.67 (3H, 3H, br s, br s, 4ꢀ-CH3, H5ꢀ), 1.70–1.85 (2H, m, H1ꢀ),
2.12 (2H, distorted q, H2ꢀ), 5.09 (1H, m, H3ꢀ), 6.00 (1H, d, J
10.5, H2), 7.13 (1H, d, J 8.5, H5), 7.70–7.88 (2H, m, H6ꢀ, H7ꢀ,
OH), 7.85 (1H, d, J 10.5, H1), 8.02 (1H, d, J 8.5, H6), 8.13, 8.23
(1H, 1H, m, m, H5ꢀ, H8ꢀ). m/z (ESI, 30V) 517 (M[37Cl] + H,
13%), 515 (M[35Cl] + H, 38), 416 (48), 275 (54), 205 (61), 149
(81), 122 (100), 104 (67), 74 (67).
Diisopropylethylamine (160 µL, 0.92 mmol), ( )-9-hydroxy-
3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-
7,10-dione 5 (60 mg, 0.18 mmol), and 1,2-dimethoxyethane
(2 mL) were added to the remaining reaction mixture (3 mL).
The resulting solution was heated at 100◦C for 7.5 h after
which time it was worked up as before to afford a red
residue (145 mg). This was subjected to flash chromatography
to afford more 7b (11 mg, 7%). Further elution of the column
with ethyl acetate/acetic acid/hexane (60/1/39) afforded as a
red solid, 3-( R,S),3ꢀ-( R,S)-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ-methyl-3ꢀ-(4ꢀꢀꢀ-
methylpent-3ꢀꢀꢀ-enyl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-3ꢀH-naphtho[2,
1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-9-
hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]
pyran-7,10-dione 2 (73 mg, 29%), mp 166–169◦C. (Found: C
74.6, H 5.1. C50H42O10 requires C 74.8, H 5.3%.) λmax/nm
(ε/M−1 cm−1) (EtOH + HCO2H) 253 (36 310), 268 (33 110),
293 (23 990), 390 (11 220). νmax/cm−1 3464m, 1650m, 1280s,
1000m. δH 1.41(6H, brs, 3-CH3, 3ꢀ-CH3), 1.51–1.57, 1.64(12H,
a series of s, br s, 3-(4ꢀ-CH3), 4ꢀꢀꢀ-CH3, 3-(H5ꢀ), H5ꢀꢀꢀ), 1.51–1.82
(4H, m, 3-(H1ꢀ), H1ꢀꢀꢀ), 1.96–2.08 (4H, m, 3-(H2ꢀ), H2ꢀꢀꢀ), 5.05
(2H, m, H3ꢀ, H3ꢀꢀꢀ), 5.91 (2H, d, J 10.5, H2, H2ꢀ), 7.02, 7.08
(2H, both d, J 8.5, isomer b and isomer a H5, H5ꢀ), 7.57, 7.64
(2H, br s, br s, OH), 7.73–7.78 (4H, m, H1, H1ꢀ, H6ꢀ, H7ꢀ), 7.93,
7.99 (2H, both d, J 8.5, isomer b and isomer a H6, H6ꢀ), 8.13–
8.16 (2H, m, H5ꢀ, H8ꢀ) [isomer a/isomer b ∼3/1]. m/z (FAB,
3NBA/MeOH) 847 (M + 2Na − 2H, 13%), 827 (M + Na + 2,
10), 826 (M + Na + 1, 14), 825 (M + Na, 18), 803 (M + H, 8),
369 (38), 213 (29). m/z (ESI, 70V) 804 (M + H + 1, 41%), 803
(M + H, 76), 243 (100), 190 (47), 147 (38), 144 (68).
3-(R,S),3ꢀ-(R,S)-8-(3ꢀ-(9ꢀ-Hydroxy-3ꢀ-methyl-3ꢀ-4ꢀꢀꢀ-
methylpent-3ꢀꢀꢀ-enyl-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-3ꢀH-
naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-
dihydronaphthalen-2ꢀ-yl)-9-hydroxy-3-methyl-3-
(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-
7,10-dione 2
9-Hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-
7,10-dione 8
Method A
A mixture of ( )-8-(3ꢀ-bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-
naphthalen-2ꢀ-yl)-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-
enyl)-3H-naphtho[2,1-b]pyran-7,10-dione 7a (53.5 mg), ( )-9-
hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]
A mixture of 2,7-dihydroxynaphthalene (16.0 g), 3-methylbut-
2-enal (9.6 mL), and pyridine (8.0 mL) was heated at 120◦C for
20 h. The mixture was cooled, diluted with ether (100 mL), and
successively washed with dilute sulfuric acid (5%, 2 × 50 mL),
water (2 × 50 mL), aqueous sodium hydrogen carbonate (10%,
2 × 50 mL), and water (2 × 50 mL). The organic phase was
dried, evaporated, and the resulting residue subjected to flash
chromatography in 20% ethyl acetate in hexane followed by
40% ethyl acetate in hexane. The major fraction (16.6 g,
73%) was recrystallized from ethyl acetate/hexane to give 3,3-
dimethyl-3H-naphtho[2,1-b]pyran-9-ol as buff-coloured crys-
tals, mp 148–149◦C (lit.[5] 146–148◦C). δH 1.48 (6H, s, 3-CH3),
4.99 (1H, br s, OH), 5.67 (1H, d, J 10, H2), 6.84–6.93 (3H, m,
pyran-7,10-dione
5 (35.4 mg), and diisopropylethylamine
(100 µL) in tetrahydrofuran (15 mL) was heated under reflux
for 72 h. The volatiles were removed under vacuum, the residue
was dissolved in ethyl acetate, and the solution washed with
aqueous hydrochloric acid (1 M) followed by water, dried, and
evaporated. The resulting residue was chromatographed twice
on Sephadex LH-20 in 50% dichloromethane in methanol. The
early eluting fractions gave 8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ-methyl-3ꢀ-(4ꢀꢀꢀ-
methylpent-3ꢀꢀꢀ-enyl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-3ꢀH-naphtho[2,

778
I. T. Crosby et al.
H1, H5, H8), 7.23 (1H, d, J 2.5, H10), 7.55, 7.63 (1H, 1H, d,
d, J 9, H6, H7). δC 27.6 (3-CH3), 76.2 (C3), 104.0 (CH), 112.7
(Cq), 115.0 (CH), 116.1 (CH), 118.3 (CH), 124.7 (Cq), 128.9
(CH), 129.2 (CH), 130.5 (CH), 131.4 (Cq), 151.6 (Cq), 154.2
(Cq). m/z (FAB, 3NBA/MeOH) 227 (M + H, 68%), 226 (92),
212 (24), 211 (100).
afford 8-(3ꢀ-bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-
9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione9a
as an orange solid (105.4 mg, 68%). δH 1.51 (6H, s, 3-CH3), 6.04
(1H, d, J 10.5, H2), 7.15 (1H, d, J 8.5, H5), 7.77–7.81 (4H, m, H1,
H6ꢀ, H7ꢀ, OH), 8.03 (1H, d, J 8.5, H60), 8.15, 8.22 (1H, 1H, m,
m, H5ꢀ, H8ꢀ). m/z (FAB, TG/G/MeOH) 494 (M[81Br] + H + 1,
16%), 493 (M[81Br] + H, 21), 491 (M[79Br] + H, 15), 413 (43),
397 (28).
N ,Nꢀ-Bis(salicylidene)ethylenediaminocobalt(ii) hydrate
(170 mg) was added to a stirred solution of 3,3-dimethyl-
3H-naphtho[2,1-b]pyran-9-ol (2.26 g) in acetonitrile (50 mL)
and oxygen bubbled through the mixture for 7.5 h. Addi-
tional N,Nꢀ-bis(salicylidene)ethylenediaminocobalt(ii) hydrate
(170 mg) was added and the bubbling of oxygen through the
mixture continued overnight. The volatiles were removed and
the residue subjected to flash chromatography in 20% ethyl
acetate in hexane then 40% ethyl acetate in hexane. The
major purple fraction (1.95 g, 81%) was recrystallized from
ethyl acetate/hexane to afford 3,3-dimethyl-3H-naphtho[2,1-
b]pyran-9,10-dione as maroon needles, mp 109–110◦C (lit.[5]
108–110◦C). δH 1.46 (6H, s, 3-CH3), 6.00 (1H, d, J 10.5, H2),
6.27 (1H, d, J 10, H8), 6.98 (1H, d, J 8, H5), 7.09 (1H, d, J 8, H6),
7.32 (1H, d, J 10.5, H1), 7.70 (1H, d, J 10, H7). δC 27.9 (3-CH3),
76.6 (C3), 119.7 (CH), 122.4 (CH), 124.3 (CH), 125.5 (Cq),
125.8 (Cq), 128.6 (Cq), 131.7 (CH), 137.2 (CH), 147.3 (CH),
156.4 (Cq), 180.9 (Cq), 181.9 (Cq). m/z (FAB, 3NBA/MeOH)
242 (M + H + 1, 52%), 241 (M + H, 100), 227 (34), 226 (21),
197 (29).
A solution of 3,3-dimethyl-3H-naphtho[2,1-b]pyran-9,10-
dione (0.91 g) in toluene (50 mL) was washed twice with a solu-
tion of sodium dithionite (5.0 g) in water (50 mL). The resulting
pale yellow solution was then added to a solution of potassium
t-butoxide in t-butanol (1 M, 20 mL) saturated with oxygen. The
resulting mixture was stirred at ambient temperature for 10 min
after which hydrochloric acid (1 M, 25 mL) was added. The
layers were separated and the organic phase was washed with
water, dried, and the solvent removed. The residue was dissolved
in ether and extracted with aqueous sodium hydrogen carbon-
ate (5%, 3 × 50 mL). The aqueous extracts were acidified with
hydrochloric acid (1 M), extracted with ethyl acetate, the extracts
dried and evaporated, and the resulting residue subjected to flash
chromatography in ethyl acetate/acetic acid/hexane (24/1/75).
The major fraction (0.592 g, 61%) was recrystallized from ethyl
acetate/hexane to give 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-
b]pyran-7,10-dione 8 as orange microneedles, mp 178–179◦C
(lit.[5] 176–177◦C). δH 1.47 (6H, s, 3-CH3), 5.99 (1H, d, J 10.5,
H2), 6.25 (1H, s, H8), 7.11 (1H, dd, J 8.5, 0.5, H5), 7.47 (1H, s,
OH), 7.76 (1H, dd, J 10.5, 0.5, H1), 7.97 (1H, d, J 8.5, H6). δC
([D6]DMSO) 27.8 (3-CH3), 77.1 (C3), 109.6 (CH), 119.4 (CH),
121.0 (Cq), 121.8 (CH), 125.2 (Cq), 126.7 (Cq), 127.9 (CH),
136.3 (CH), 157.5 (Cq), 160.2 (Cq), 183.8 (Cq), 184.5 (Cq). m/z
(FAB, 3NBA/MeOH) 258 (M + H + 1, 50%), 257 (M + H, 100),
256 (42), 243 (21), 242 (33), 241 (75), 213 (23).
9-Hydroxy-8-(3ꢀ-9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 3
A mixture of 8-(3ꢀ-bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-
2ꢀ-yl)-9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-
dione 9a (15.8 mg), 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione 8 (9.2 mg), and diisopropylethylamine (35 µL)
in tetrahydrofuran (10 mL) was heated under reflux for 46 h.
The volatiles were removed under vacuum, the residue dis-
solved in ethyl acetate, and the solution washed with aqueous
hydrochloric acid (1 M) followed by water, dried, and evapo-
rated. The resulting residue was chromatographed on Sephadex
LH-20 in methanol and rechromatographed on Sephadex LH-
20 in 10% dichloromethane in methanol. The early eluting
fractions gave 9-hydroxy-8-(3ꢀ-9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-1ꢀ,4ꢀ-
dioxo-1ꢀ,4ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione 3 (15.1 mg, 80%) as an orange solid, mp 300◦C
(dec.). (Found: C 72.0, H 4.0. C40H26O10 requires C 72.1,
H 3.9%.) νmax/cm−1 3344, 1662, 1592, 1560. δH 1.46 (12H,
s, 3-CH3, 3ꢀ-CH3), 5.96 (2H, d, J 10.5, H2, H2ꢀ), 7.05, 7.10 (2H,
both d, J 8.5, isomer b and isomer a H5, H5ꢀ), 7.53 (2H, br s,
OH), 7.68, 7.69 (2H, both d, J 10.5, isomer a and isomer b H1,
H1ꢀ), 7.74–7.77 (2H, m, H6ꢀ, H7ꢀ), 7.95, 8.00 (2H, both d, J
8.5, isomer b and isomer a H6, H6ꢀ), 8.14–8.17 (2H, m, H5ꢀ,
H8ꢀ) [isomer a/isomer b ∼3/1]. m/z (FAB, 3NBA/MeOH) 667
(M + H).
8-(3ꢀ-(9ꢀ-Acetoxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-
dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydronaphthalene-2ꢀ-yl)-3,3-dimethyl-3H-naphtho
[2,1-b]pyran-7,10-dion-9-yl Acetate 11 and
8-(5ꢀ-Acetoxy-3ꢀ,3ꢀ-dimethyl-2ꢀ,7ꢀ,9ꢀ-trioxo-7ꢀ,9ꢀ-dihydro-
2ꢀH,3ꢀH-spiro[cyclopenta[f]chromene-8ꢀ,3ꢀ-naphtho[1,2-
b]furan]-4ꢀ-yl)-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-
dion-9-yl Acetate 12
A solution of 2,3-dibromo-1,4-naphthoquinone[6] 6a (820 mg),
9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 5
(1.4 g), and diisopropylethylamine (4.5 mL) in 1,2-dimethoxy-
ethane (20 mL) was heated at reflux for 5 h. The resulting
dark solution was washed sequentially with dilute aqueous
hydrochloric acid (1 M) and water then dried and concentrated.
The residue was dissolved in dichloromethane (30 mL) and
acetic anhydride (1 mL) and pyridine (8 drops) were added
and the mixture allowed to stand overnight. The dark yellow/
brown solution was washed with aqueous hydrochloric acid
(1 M) and water, and then dried and concentrated. The residue
was subjected to flash chromatography in hexane/ethyl acetate
(4/1) to afford the trimeric quinone diacetate (RF 0.33) as an
orange solid (1.39 g, 72%). Recrystallization from ethyl acetate/
hexane afforded 8-(3ꢀ-(9ꢀ-acetoxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,
8-(3ꢀ-Bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-
2ꢀ-yl)-9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione 9a
A solution of 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-
7,10-dione 8 (102.6 mg), 2,3-dibromo-1,4-naphthoquinone[6]
6a (156 mg), and diisopropylethylamine (86 µL) in tetrahydro-
furan (10 mL) was heated under reflux overnight. The volatiles
were removed under vacuum and the residue subjected to flash
chromatography in ethyl acetate/acetic acid/hexane (24/1/75) to

Naphthoquinone Analogues of Conocurvone
779
4ꢀ-dihydronaphthalene-2ꢀ-yl)-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dion-9-yl acetate 11 as red prisms, mp 252–254◦C
(dec.). (Found: C 70.6, H 4.0. C44H30O12 requires C 70.4,
H 4.0%.) λmax/nm (ε/M−1 cm−1) 205 (43 650), 233 (52 480),
274 (30 900), 458 (6460). νmax/cm−1 1780, 1674, 1650, 1592,
1562. δH 1.47, 1.49 (6H, 6H, s, s, 3-CH3, 3ꢀ-CH3), 2.13 (6H,
s, OAc), 5.90, 6.04 (2H, both d, J 10.5, H2, H2ꢀ, isomer a, iso-
mer b), 7.03, 7.09 (2H, both d, J 8.5, H5, H5ꢀ, isomer b, isomer
a), 7.55, 7.59 (2H, partially obscured d, d, J 10.4, H1, H1ꢀ, iso-
mer b, isomer a), 7.79–7.82 (2H, m, H6ꢀ, H7ꢀ), 7.95 (2H, d, J
8.5, H6, H6ꢀ), 8.16–8.19 (2H, m, H5ꢀ, H8ꢀ) (isomer a/isomer b
∼20/1). m/z (FAB, 3NBA/CHCl3) 753 (M + H + 2, 11%), 752
(M + H + 1, 21), 751 (M + H, 15), 709 (31), 669 (21), 668 (43),
667 (76), 666 (29).
Reaction of 2,3-dichloro-1,4-naphthoquinone 6b (1.0 g),
9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 5
(2.4 g), and diisopropylethylamine (7 mL) in 1,2-dimethoxy-
ethane (25 mL) under identical conditions to that describe above
gave, after acetylation, the diacetate 11 (2.45 g, 74%).
In both instances, employing either the 2,3-dibromo-1,4-
naphthoquinone 6a or 2,3-dichloro-1,4-naphthoquinone 6b, a
second darker red band was isolated after chromatography
(RF 0.18) (<20%).
hydrochloric acid (1 M), dried, and partially concentrated (20–
30 mL). The mixture was filtered and the filter cake washed with
cold chloroform (350 mL) followed by ethyl acetate until the fil-
trate was colourless. The orange solid was dried under suction
to afford crude 3 (5.90 g, 50% yield, 91.4% pure by HPLC), mp
292–296◦C (dec.). The material can purified by taking the crude
3 (250 mg) and boiling in acetic acid (5 mL) for 30 min, filtering,
washing the filter cake with hot acetic acid until the washings
were colourless, followed by hot ethanol to give 3 (96.2% by
HPLC). A portion of the solid (100 mg) was dissolved in hot
N,N-dimethylformamide (50 mL) and water (20 mL) carefully
added. Filtration of the resulting precipitate afforded 3 as red
microprisms (97.6% by HPLC), mp >320◦C (dec.). Alterna-
tively, preparative HPLC of 3 (96.2% by HPLC) gave material
that assayed at 99.0% (by HPLC).
( )-8-(3ꢀ-(9ꢀ-Hydroxy-3ꢀ,3ꢀ-dimethyl-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-
dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-9-hydroxy-3-methyl-3-
(4ꢀ-methylpent-3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-
7,10-dione 10
Method A
Slow recrystallization from ethyl acetate afforded 8-(5ꢀ-
acetoxy-3ꢀ,3ꢀ-dimethyl-2ꢀ,7ꢀ,9ꢀ-trioxo-7ꢀ,9ꢀ-dihydro-2ꢀH,3ꢀH-
spiro[cyclopenta[f]chromene-8ꢀ,3ꢀ-naphtho[1,2-b]furan]-4ꢀ-yl)-
3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dion-9-yl acetate
12 as red microprisms, mp 205–208◦C (softens), 275◦C (dec.).
λmax/nm (ε/M−1 cm−1) 233 (56 230), 266 (51 290), 374 (6030).
νmax/cm−1 1816, 1780, 1770, 1736, 1706, 1666, 1646, 1640,
1560. δH 1.47, 1.48, 1.55, 1.59 (3H, 3H, 3H, 3H, s, s, s, s, 3-
CH3, 3ꢀ-CH3), 2.14, 2.22 (3H, 3H, s, s, OAc), 5.88, 5.89 (1H,
1H, d, d, J 10, 10.5, H2, H2ꢀ), 7.06 (1H, d, J 8, H5 or H5ꢀ), 7.26
(1H, d, J 10, H1 or H1ꢀ), 7.35 (1H, d, J 8.5, H5 or H5ꢀ), 7.50
(1H, d, J 10.5, H1 or H1ꢀ), 7.63–7.77 (4H, m, d, H6ꢀ, H7ꢀ, H8ꢀ,
H9ꢀ), 7.85 (1H, d, J 8.5, H6 or H6ꢀ), 8.17 (1H, br d, J 8, H6
or H6ꢀ). m/z (FAB, 3NBA/MeOH) 753 (M + H + 2, 2%), 752
(M + H + 1, 4%), 751 (M + H, 5%), 750 (M + H − 1, 2%), 711
(15), 710 (39), 709 (52), 708 (14), 668 (20), 667 (47), 666 (38).
A mixture of ( )-8-(3ꢀ-bromo-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-
naphthalen-2ꢀ-yl)-9-hydroxy-3-methyl-3-(4ꢀ-methylpent-3ꢀ-
enyl)-3H-naphtho[2,1-b]pyran-7,10-dione 7a (51.2 mg), 9-
hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione
5
(28.4 mg), and diisopropylethylamine (100 µL) in tetrahydro-
furan (15 mL) was heated under reflux for 48 h. The volatiles
were removed under vacuum, the residue dissolved in ethyl
acetate, and the solution washed with aqueous hydrochlo-
ric acid (1 M) followed by water, dried, and evaporated. The
resulting residue was chromatographed on Sephadex LH-20 in
10% dichloromethane in methanol and rechromatographed on
SephadexLH-20in50%dichloromethaneinmethanol.Theearly
eluting fractions gave ( )-8-(3ꢀ-9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-1ꢀ,4ꢀ-
dioxo-1ꢀ,4ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-9-hydroxy-3-methyl-3-(4ꢀ-methyl-
pent-3ꢀ-enyl)-3H-naphtho[2,1-b]pyran-7,10-dione 10 as an
orange solid (10.2 mg, 15%), mp 151–156◦C. This was purified
by taking up the product in minimal acetic acid and precipitating
with ether, mp 199–202◦C. (Found: C 73.5, H 4.7. C45H34O10
requires C 73.6, H 4.7%.) λmax/nm (ε/M−1 cm−1) 274 (74 130),
292sh (61 660), 392 (28 180). νmax/cm−1 3350w, 1656m, 1274s,
1000m. δH 1.41(6H, brs, 3-CH3, 3ꢀ-CH3), 1.51–1.57, 1.64(12H,
a series of s, br s, 3-(4ꢀ-CH3), 4ꢀꢀꢀ-CH3, 3-(H5ꢀ), H5ꢀꢀꢀ), 1.51–1.82
(4H, m, 3-(H1ꢀ), H1ꢀꢀꢀ), 1.96–2.08 (4H, m, 3-(H2ꢀ), H2ꢀꢀꢀ), 5.05
(2H, m, H3ꢀ, H3ꢀꢀꢀ), 5.91 (2H, d, J 10.5, H2, H2ꢀ), 7.02, 7.08
(2H, both d, J 8.5, isomer b and isomer a H5, H5ꢀ), 7.57, 7.64
(2H, br s, br s, OH), 7.73–7.78 (4H, m, H1, H1ꢀ, H6ꢀ, H7ꢀ), 7.93,
7.99 (2H, both d, J 8.5, isomer b and isomer a H6, H6ꢀ), 8.13–
8.16 (2H, m, H5ꢀ, H8ꢀ) [isomer a/isomer b ∼3/1]. m/z (ESI, 30V)
736 (M + H, 100%). m/z (FAB, 3NBA/MeOH) 737 (M + H + 2,
44%), 736 (M + H + 1, 34), 735 (M + H, 19).
9-Hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-
dioxo-1ꢀ,4ꢀ-dihydronaphthalene-2ꢀ-yl)-3,3-dimethyl-
3H-naphtho[2,1-b]pyran-7,10-dione 3
To a solution of the diacetate 11 (300 mg) in dichloromethane
(15 mL) was added freshly ground aluminium chloride (810 mg)
and the resulting dark purple suspension was stirred for 1 h. The
suspension was diluted with further dichloromethane (100 mL)
and then washed sequentially with aqueous oxalic acid solu-
tion (5%, 2 × 150 mL) and water. The orange/brown solution
was partially concentrated (∼30 mL) and allowed to boil on a
steambath. Trituration of the mixture with hexane afforded 3 as
an orange/red amorphous solid (206 mg, 77%), mp 299–302◦C
(dec.).
Larger Scale Synthesis and Purification of 3
Method B
Diisopropylethylamine (30 mL) was added to a stirred solution
of 2,3-dichloro-1,4-naphthoquinone 6b (4.0 g) and 9-hydroxy-
3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 5 (9.4 g) in
1,2-dimethoxyethane (50 mL) and the resulting mixture was
heated at reflux for 6 h. The dark mixture was allowed to
cool, diluted with dichloromethane, washed with dilute aqueous
A mixture of ( )-8-(3ꢀ-chloro-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-
naphthalen-2ꢀ-yl)-9-hydroxy-3-methyl-3-(15-methylpent-14-
enyl)-3H-naphtho[2,1-b]pyran-7,10-dione
0.796 mmol), 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-
7,10-dione 8 (204 mg, 0.796 mmol), and diisopropylethylamine
7b
(410 mg,

780
I. T. Crosby et al.
(1.4 mL) in 1,2-dimethoxyethane (25 mL) was heated under
reflux for 4 h. The reaction mixture was cooled and acidified
with aqueous hydrochloric acid (1 M, 50 mL). The mixture was
extracted with ethyl acetate (3 × 50 mL), dried, and the solvent
evaporated. Flash chromatography of the resulting residue, with
ethyl acetate/acetic acid/hexane (39/1/60) as eluent, gave the
( )-asymmetric trimer 2 (280 mg, 48%).
9-Hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-1ꢀ,2ꢀ,7ꢀ,10ꢀ-
tetrahydro-7ꢀ,10ꢀ-dioxo-3ꢀH-naptho[2,1-b]pyran-8ꢀ-yl)-
1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalene-2ꢀ-yl)-3,3-dimethyl-
1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione 16
To
a stirred solution of the diacetate 15 (65 mg) in
dichloromethane (4 mL) was added ground aluminium chlo-
ride (200 mg) and the resulting dark suspension was stirred
at room temperature for 75 min. Dilution of the mixture with
dichloromethane (30 mL) followed by washing with aqueous
oxalic solution (5%, 2 × 60 mL) and water, gave an orange solu-
tion that was dried and partially concentrated to an approximate
volume of 5 mL.The solution was allowed to boil on a steam bath
and triturated with hexane. The precipitate that formed on stand-
ing was filtered off and washed with a cold mixture of hexane/
dichloromethane (1/1) to afford 9-hydroxy-8-(3ꢀ-(9ꢀhydroxy-
3ꢀ,3ꢀ-dimethyl-1ꢀ,2ꢀ,7ꢀ,10ꢀ-tetrahydro-7ꢀ,10ꢀ-dioxo-3ꢀH-naptho
[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalene-2ꢀ-yl)-
3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione
16 as a mustard yellow amorphous solid (43 mg, 75%), mp
278–81◦C. (Found: [M + H]+ 671.1914. C40H31O10 requires
671.1917.) νmax/cm−1 3340, 1662, 1566. δH ([D6]DMSO) 1.30
(12H, s, 3-CH3, 3ꢀ-CH3), 1.80 (4H, br t, H2, H2ꢀ), 3.14 (4H, br
t, H1, H1ꢀ), 7.08, 7.16 (2H, both d, J 8.5, isomer b and isomer a
H5, H5ꢀ), 7.67, 7.78 (2H, both d, J 8.5, isomer b and isomer a H6,
H6ꢀ), 7.96 (2H, m, H6ꢀ, H7ꢀ), 8.80 (2H, m, H5ꢀ, H8ꢀ) [isomer a/
isomer b ∼2/1]. m/z (FAB, 3NBA/CHCl3) 672 (M + H + 2, 8%),
671 (M + H, 10).
9-Hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho
[2,1-b]pyran-7,10-dione 14
A mixture of 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-
7,10-dione 8 (1.20 g) and platinum(iv) oxide (125 mg) in ethyl
acetate (30 mL) was stirred under hydrogen for 3.5 h. The dark
mixture was allowed to stir exposed to air for 30 min before fil-
tration through a plug of Celite. Concentration of the filtrate gave
a yellow residue which was subjected to flash chromatography
in hexane/ethyl acetate (7/3) + 1% acetic acid. Recrystalliza-
tion form ethyl acetate/hexane gave 9-hydroxy-3,3-dimethyl-1,2-
dihydro-3H-naphtho[2,1-b]pyran-7,10-dione 14 (948 mg, 79%)
as yellow needles, mp 155◦C (subl.), >177◦C (dec.). νmax/cm−1
3328, 3148, 3108, 1656, 1628, 1566. δH 1.38 (6H, s, 3-CH3),
1.89 (2H, br t, J 6.5, H2), 3.29 (2H, t, J 6.5, H3), 6.25 (1H, s,
H8), 7.13 (1H, d, J 8.5, H5), 7.47 (1H, s, OH), 7.97 (1H, d, J
8.5, H6). m/z (FAB, 3NBA/MeOH) 261 (M + H + 2, 11%), 260
(M + H + 1, 27), 259 (M + H, 51).
9-N,N-Dimethylcarbamyloxy-8-(3ꢀ-(9ꢀ-N,N-
dimethylcarbamyloxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naptho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
1ꢀ,4ꢀ-dihydronaphthalene-2ꢀ-yl)-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 17
9-Acetoxy-8-(3ꢀ-(9ꢀ-acetoxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
1ꢀ,2ꢀ,7ꢀ,10ꢀ-tetrahydro-3H-naptho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-
dioxo-1ꢀ,4ꢀ-dihydronaphthalene-2ꢀ-yl)-3,3-dimethyl-1,2-
dihydro-3H-naphtho[2,1-b]pyran-7,10-dione 15
A solution of 2,3-dichloronaphthoquinone 6b (100 mg), 9-
hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,
10-dione 14 (238 mg), and diisopropylethylamine (0.75 mL)
in 1,2-dimethoxyethane (4 mL) was heated at reflux for 4 h.
The resulting dark solution was allowed to cool, washed
with aqueous hydrochloric acid (1 M), dried, and concentrated.
The residue was dissolved in a mixture of dichloromethane
(10 mL), acetic anhydride (10 drops), and pyridine (3 drops)
and the mixture allowed to stand for 30 min. The dark yellow/
brown solution was washed sequentially with aqueous
hydrochloric acid (1 M) and water, dried, and concentrated.
The residue was subjected to flash chromatography in hexane/
ethyl acetate (4/1) to afford the trimer as a yellow solid
(226 mg, 68%). Hot charcoal filtration of an ethyl acetate
solution of the trimer followed by recrystallization from
ethyl acetate/hexane afforded 9-acetoxy-8-(3ꢀ-(9ꢀ-acetoxy-3ꢀ,3ꢀ-
dimethyl-7ꢀ,10ꢀ-dioxo-1ꢀ,2ꢀ,7ꢀ,10ꢀ-tetrahydro-3H-naptho[2,1-b]
pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-
dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione 15
as yellow/orange prisms. (Found: C 70.2, H 4.7. C44H44O12
requires C 70.0, H 4.5%.) νmax/cm−1 1784, 1738, 1672, 1650,
1582, 1566. δH 1.36, 1.38 (6H, 6H, s, s, 3-CH3, 3ꢀ-CH3),
1.83 (4H, t, J 6.5, H2, H2ꢀ), 2.13 (6H, s, OAc), 3.21 (4H,
br m, H1, H1ꢀ), 7.05, 7.11 (2H, both d, J 8.5, isomer b and
isomer a H5, H5ꢀ), 7.78–7.82 (2H, m, H6ꢀ, H7ꢀ), 7.91, 7.95
(2H, partially obscured d, d, J 8.5, isomer b and isomer a
H6, H6ꢀ), 8.16–8.19 (2H, m, H5ꢀ, H8ꢀ) [isomer a/isomer b
∼10/1]. m/z (FAB, 3NBA/MeOH) 756 (M + H + 1, 22%), 755
(M + H, 18), 714 (22), 713 (40), 673 (24), 672 (57), 671 (100),
670 (36).
N,N-Dimethylcarbamyl chloride (4 drops) was added to a stirred
solution of dihydroxytrimer 3 (67 mg) in pyridine (1 mL) under
nitrogen. The solution was heated at reflux for 75 min and then
allowed to cool. Dilution of the mixture with dichloromethane
(20 mL) followed by washing with dilute aqueous hydrochloric
acid (1 M) and then water gave, after drying and concentration,
an orange solid that was subjected to flash chromatography
in hexane/ethyl acetate (7/3). The major band gave biscar-
bamate (45 mg, 58%), which was recrystallized from ethyl
acetate/hexane to afford 9-N,N-dimethylcarbamyloxy-8-(3ꢀ-(9ꢀ-
N,N-dimethylcarbamyloxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-
dihydro-3ꢀH-naptho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-1ꢀ,4ꢀ-dihydro-
naphthalene-2ꢀ-yl)-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-
dione 17 as orange microneedles, mp 272–5◦C (dec.). (Found:
C 68.2, H 4.4, N 3.3. C46H36N2O12 requires C 68.3, H 4.5,
N 3.5%.) νmax/cm−1 3450, 1742, 1672, 1652, 1592, 1562. δH
1.45, 1.46 (6H, 6H, s, s, 3-CH3, 3ꢀ-CH3), 2.59, 2.82 (6H, 6H, br
s, br s, NMe2), 5.86 (2H, d, J 10.5, H2, H2ꢀ), 7.06 (2H, d, J 8.5,
H5, H5ꢀ), 7.67 (2H, d, J 10.5, H1, H1ꢀ), 7.77–7.80 (2H, m, H6ꢀ,
H7ꢀ), 7.91 (2H, d, J 8.5, H6, H6ꢀ), 8.16–8.19 (2H, m, H5ꢀ, H8ꢀ).
m/z (FAB, 3NBA/CHCl3) 810 (M + H + 1, 13%), 809 (M + H,
23), 808 (M + H − 1, 29) 792 (8), 764 (15), 719 (15), 632 (28).
2,3-Dichloro-6-hydroxy-1,4-naphthoquinone[9] 18
trans-1-Methoxy-3-trimethylsilyloxybuta-1,3-diene[10]
(0.93 mL, 4.7 mmol) was added dropwise to a solution of
2,3,6-trichloro-1,4-benzoquinone 19 (1.0 g, 4.7 mmol) in dry
dichloromethane (50 mL) and the mixture stirred for 5 min, after
which the solvent was evaporated. The resultant residue was
20

Naphthoquinone Analogues of Conocurvone
781
dissolved in tetrahydrofuran (75 mL) and concentrated aqueous
hydrochloric acid (5 drops) added. A solution of sodium acetate
(300 mg) in ethanol (25 mL) was then added to the above solu-
tion, and the resultant mixture heated on a steam bath for 15 min.
The mixture was allowed to cool, concentrated under reduced
pressure, diluted with water, and the product extracted with
ethyl acetate. The extracts were dried (Na2SO4) and evaporated
to give 2,3-dichloro-6-hydroxy-1,4-naphthoquinone 18 (1.12 g,
97%), mp 230–233◦C (lit.[9] 235–236◦C). The product was used
without purification for further reactions.
dichloromethane (20 mL) and acetic anhydride (1 mL), and
pyridine (10 drops) added. The mixture was stirred at room tem-
perature for 1 h, diluted with dichloromethane (20 mL), and the
organic phase washed with aqueous hydrochloric acid (20 mL),
saturated brine, dried over sodium sulfate, and the volatiles
removed under vacuum. The residue was purified by flash
chromatography (ethyl acetate/hexane/acetic acid, 30/70/0.1) to
give the crude diacetate (110 mg, 48%). The crude diacetate
(70 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL),
cooled in ice, and freshly ground aluminium trichloride (180 mg,
1.35 mmol) added. After 20 min the mixture was diluted with
dichloromethane (30 mL) and then washed with aqueous oxalic
acid (3 × 30 mL, 5%). The organic phase was dried over sodium
sulfate and concentrated to ∼4 mL.This solution was then heated
on a steam bath and petroleum spirit (5 mL) slowly added to give
9-hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-
dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-6ꢀ-methoxy-
1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione 24 (14 mg, 22%). (Found: C 70.8, H 4.3.
C41H28O11 requires C 70.7, H 4.1%.) δH 1.47 (12H, s, 3-CH3,
3ꢀ-CH3), 5.97 (2H, d, J 10.5, H2, H2ꢀ), 7.04–7.13 (2H, m, H5,
H5ꢀ), 7.23 (1H, dd, J 8.5, 2.5, H7ꢀ), 7.55 (2H, br, OH), 7.59 (1H,
d, J 2.5, H5ꢀ), 7.69, 7.70 (2H, both d, J 10.5, H1, H1ꢀ), 7.94–8.03
(2H, m, H6, H6ꢀ), 8.11 (1H, d, 8.5, H8ꢀ). m/z (ESI, 70V) 698
(M + H + 1, 44%), 697 (M + H, 100), 441 (41).
2,3-Dichloro-6-n-propyloxy-1,4-naphthoquinone 22
Silver(i) oxide (1.2 g, 5.18 mmol) was added to a solution
of 2,3-dichloro-6-hydroxy-1,4-naphthoquinone[9] 18 (606 mg,
2.49 mmol) and 1-bromopropane (560 µL, 6.15 mmol) in dry
dichloromethane (20 mL). The mixture was stirred overnight
under nitrogen at ambient temperature after which additional
silver(i) oxide (1.0 g, 4.32 mmol) and 1-bromopropane (1.0 mL,
10.98 mmol) were added. Stirring was maintained for a further
70 h after which the mixture was filtered through a pad of Celite
and the residue washed with ethyl acetate and dichloromethane.
The filtrate and washings were combined and the sol-
vents removed under vacuum to give, after recrystallization
from ethyl acetate/hexanes, 2,3-dichloro-6-n-propyloxy-1,4-
naphthoquinone 22 (620 mg, 87%). νmax/cm−11680s, 1598m,
1578s, 1562m. δH 1.07 (3H, t, J 7.5, OCH2CH2CH3), 1.81–1.93
(2H, m, OCH2CH2CH3), 4.08 (2H, t, J 6.5, OCH2CH2CH3),
7.23 (1H, dd, J 8.5, 2.5, H7), 7.59 (1H, d, J 2.5, H5), 8.14 (1H,
d, J 8.5, H8).
9-Hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
6ꢀ-n-propyloxy-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-
dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 25
Diisopropylethylamine (0.3 mL, 1.7 mmol) was added to a
solution of 2,3-dichloro-6-n-propyloxy-1,4-naphthoquinone 22
(50 mg, 0.18 mmol) and monomer 8 (92 mg, 0.36 mmol) in 1,2-
dimethoxyethane (3.5 mL) and the reaction refluxed for 8 h
under nitrogen. The reaction mixture was cooled, poured into
ethyl acetate (20 mL), and aqueous hydrochloric acid (1 M)
added, the organic phase separated, dried (Na2SO4), and the
volatiles were removed under vacuum. The resulting residue
(137 mg) was purified in two ways:
2,3-Dichloro-6-n-pentyloxy-1,4-naphthoquinone 23
Silver(i) oxide (1.5 g, 6.27 mmol) was added to a solution
of 2,3-dichloro-6-hydroxy-1,4-naphthoquinone[9] 18 (0.80 g,
3.29 mmol), and 1-iodopentane (510 µL, 3.91 mmol) in dry
dichloromethane (20 mL), and the mixture stirred under nitro-
gen at room temperature for 19.5 h. The mixture was filtered
through a pad of Celite, and the residue washed with ethyl
acetate and dichloromethane. The filtrate and washings were
combined and the solvents removed under vacuum. Flash
chromatography (10–100% ethyl acetate in hexanes) of the
residue gave 2,3-dichloro-6-n-pentyloxy-1,4-naphthoquinone
23 (573 mg, 56%). δH 0.95 (3H, t, J 7, OCH2(CH2)3CH3),
1.33–1.54 (4H, m, OCH2CH2(CH2)2CH3), 1.79–1.81 (2H, m,
OCH2CH2(CH2)2CH3), 4.12 (2H, t, J 6.5, OCH2(CH2)3CH3),
7.23 (1H, dd, J 8.5, 2.5, H7), 7.59 (1H, d, J 2.5, H5), 8.12 (1H,
d, J 8.5, H8).
Method 1
A sample (35 mg) was subjected to preparative HPLC
(70% A, 30% B). Fractions that showed, by analytical HPLC
(70% A, 30% B), to be one compound (Rt 10.9 min) were
combined; however, this required further separation by prepar-
ative TLC (ethyl acetate/hexane/acetic acid, 74/24/1). Extrac-
tion of base-line material from the silica with ethyl acetate
and dichloromethane gave 9-hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-
dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-
8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-6ꢀ-n-propyloxy-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-
3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 25 (6 mg,
18%), mp 322◦C (dec.). (Found: M + H (FAB, PEG), 725.2020.
C43H33O11 requires 725.2023.) λmax/nm (ε/M−1 cm−1) 220
(47 860), 272 (46 770), 392 (10 230). νmax/cm−1 3452m, 1658m,
1644m, 1594m, 1284s. δH 1.06 (3H, t, J 7, CH2CH3), 1.47 (12H,
s, 3-CH3, 3ꢀ-CH3), 1.82–1.95 (2H, m, OCH2CH2CH3), 4.07
(2H, t, J 7, OCH2), 5.97 (2H, d, J 10.5, H2 and H2ꢀ), 7.02–
7.22 (2H, m, H5, H5ꢀ and H7ꢀ), 7.54–7.60 (1H, m, H5ꢀ), 7.69
(2H, d, J 10.5, H1 and H1ꢀ), 7.90–8.15 (3H, m, H6, H6ꢀ, H8ꢀ).
m/z (ESI, 70V) 726 (M + H + 1, 11%), 725 (M + H, 23), 165
(41), 149 (100), 121 (41).
9-Hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
6ꢀ-methoxy-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-dimethyl-
3H-naphtho[2,1-b]pyran-7,10-dione 24
Diisopropylethylamine (508 µL, 2.92 mmol) was added to
a solution of 2,3-dichloro-6-methoxy-1,4-naphthoquinone[9]
21 (75 mg, 0.292 mmol) and 9-hydroxy-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 8 (157 mg, 0.613 mmol). The
mixture heated at reflux for 7 h and then left to stir overnight.
The mixture was then partitioned between ethyl acetate (40 mL)
and aqueous hydrochloric acid (40 mL, 1 M). The organic phase
was separated and washed with aqueous hydrochloric acid
(2 × 30 mL, 1 M), dried over sodium sulfate, and the volatiles
were removed under vacuum. The residue was dissolved in

782
I. T. Crosby et al.
Method 2
2,3,5-Trichloro-6-methoxy-1,4-naphthoquinone[9] 29
A sample (60 mg) was subjected to preparative TLC in ethyl
acetate/hexane/acetic acid (74/24/1). Extraction of base-line
material from the silica with ethyl acetate and dichloromethane
gave 20 mg of a black solid. Preparative HPLC (65% A, 35% B)
gave 25 (10 mg, 18%).
The crude preceding compound 28 (226 mg) was dissolved
in dichloromethane (40 mL) and iodomethane (2 mL), and sil-
ver(i) oxide (250 mg) added. The mixture was stirred overnight
after which additional iodomethane (1 mL) and silver(i) oxide
(100 mg) was added.After 6 h of further stirring the mixture was
filtered through a pad of Celite and the filtrate evaporated to give
a yellow solid that was purified by flash chromatography and
recrystallized from ethyl acetate/hexane to give 2,3,5-trichloro-
6-methoxy-1,4-naphthoquinone 29 (223 mg, 94%).
9-Hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-
6ꢀ-n-pentyloxy-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-dimethyl-
3H-naphtho[2,1-b]pyran-7,10-dione 26
Diisopropylethylamine (1.11 mL, 6.4 mmol) was added to a
solution of 2,3-dichloro-6-n-pentyloxy-1,4-naphthoquinone 23
(200 mg, 0.64 mmol) and monomer 8 (335 mg, 1.31 mmol) in
1,2-dimethoxyethane (12 mL) and the reaction mixture refluxed
for 8 h under nitrogen. The reaction mixture was then cooled,
poured into aqueous hydrochloric acid (1 M), and extracted
with ethyl acetate. The organic phase was separated, dried,
and the volatiles were removed under vacuum to leave the
crude product (480 mg). A filtered sample (23 mg) of this
residue was subjected to preparative HPLC (70% A, 30% B).
Fractions shown to be pure by analytical HPLC (80% A,
20% B, Rt 8.9 min) were combined to give 9-hydroxy-8-(3ꢀ-(9ꢀ-
hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho
[2,1-b]pyran-8ꢀ-yl)-1ꢀ,4ꢀ-dioxo-6ꢀ-n-pentyloxy-1ꢀ,4ꢀ-dihydro-
naphthalen-2ꢀ-yl)-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-
dione 26 as an orange powder (3.1 mg, 13%), mp 298◦C (dec.).
(Found: [M + H]+ (FAB, PEG) 753.232. C45H37O11 requires
753.233.) λmax/nm (ε/M−1 cm−1) 211 (32 360), 269 (23 990),
292sh (21 380), 392 (6920). νmax/cm−1 3452m, 1660m, 1646m,
1632m, 1594m, 1284s. δH 0.94 (3H, t, J 7, CH2CH3), 1.32–1.63
(4H, m, 2 × CH2), 1.47 (12H, s, 3-CH3, 3ꢀ-CH3), 1.78–1.88 (2H,
m, CH2CH2O), 4.11 (2H, t, J 6.5, OCH2), 5.96 (2H, d, J 10.5, H2
and H2ꢀ), 7.05, 7.11 (2H, partially obscured d, d, J 8.5, H5 and
H5ꢀ isomer b and isomer a), 7.18–7.22 (1H, m, H7ꢀ), 7.52–7.71
(5H, m, H1 and H1ꢀ, H5ꢀ, OH), 7.95, 8.01 (2H, partially obscured
d, d, J 8.5, H6 and H6ꢀ isomer b and isomer a), (8.09 d, J 8, H8ꢀ)
[isomer a/isomer b ∼1/2]. m/z (ESI, 100V) 755 (M + H + 2,
3%), 754 (M + H + 1, 9), 753 (M + H, 14), 240 (66), 91 (100).
Fractions from HPLC that were shown, by analytical
HPLC (80% A, 20% B), to be a mixture of two compounds
and were combined and subjected to preparative TLC (ethyl
acetate/hexane/acetic acid, 74/24/1). Extraction from the base-
linesilicawithethylacetateanddichloromethanegaveadditional
26 (6.5 mg, 28%).
9-Hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-5ꢀ-chloro-
1ꢀ,4ꢀ-dioxo-6ꢀ-methoxy-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-
3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 31
Diisopropylethylamine (508 µL, 2.92 mmol) was added to
a solution of 2,3,5-trichloro-6-methoxy-1,4-naphthoquinone
29 (84 mg, 0.288 mmol) and 9-hydroxy-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 8 (155 mg, 0.605 mmol), the
mixture heated under reflux for 6.5 h and then left to stir
overnight. The mixture was then heated for a further 6 h and
then partitioned between ethyl acetate (40 mL) and aqueous
hydrochloric acid (40 mL, 1 M). The organic phase was sepa-
rated and washed with aqueous hydrochloric acid (30 mL, 1 M),
dried over sodium sulfate, and the volatiles removed under vac-
uum. The residue was dissolved in dichloromethane (15 mL)
and acetic anhydride (1 mL) and pyridine (10 drops) added. The
mixture was stirred at room temperature for 4 h, partitioned
between ethyl acetate (20 mL) and aqueous hydrochloric acid
(20 mL), the organic phase washed with aqueous hydrochloric
acid (20 mL), saturated brine (20 mL), dried over sodium sul-
fate, and the volatiles were removed under vacuum. The residue
was purified by flash chromatography (ethyl acetate/hexane,
1/2; and then ethyl acetate/hexane/acetic acid, 1/1/0.01) to
give the crude diacetate 30 (46 mg, 48%). δH 1.46, 1.48 (6H,
6H, s, s, 3-CH3, 3ꢀ-CH3), 2.12 (6H, s, OAc), 4.05 (3H, s,
OCH3), 5.89 (2H, d, J 10.5, H2, H2ꢀ), 7.08 (2H, d, J 8.5,
H5, H5ꢀ), 7.27 (1H, partially obscured d, H7ꢀ), 7.57 (2H, d,
J 10.5, H1, H1ꢀ), 7.92–7.95 (2H, m, H6, H6ꢀ), 8.18 (1H, d,
J 8.5, H8ꢀ).
The crude diacetate 30 (14 mg, 0.017 mmol) was dis-
solved in dichloromethane (5 mL), cooled in ice, and freshly
ground aluminium trichloride (34 mg, 0.255 mmol) added.
After 15 min the mixture was diluted with dichloromethane
(20 mL) and then washed with aqueous oxalic acid (2 × 20 mL,
5%). The organic phase was dried over sodium sulfate and
evaporated under vacuum to give the crude product 31
(11.5 mg, 92%). This was purified by dissolving in ethyl
acetate (0.5 mL) and slowly adding petroleum spirit (1 mL)
to give 9-hydroxy-8-(3ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-5ꢀ-chloro-1ꢀ,4ꢀ-
dioxo-6ꢀ-methoxy-1ꢀ,4ꢀ-dihydronaphthalen-2ꢀ-yl)-3,3-dimethyl-
3H-naphtho[2,1-b]pyran-7,10-dione 31 as a brown solid.
(Found: [M + H[35Cl]]+ (FAB, PEG) 731.136. C41H2835ClO11
requires 731.132.) δH 1.45–1.52 (12H, overlapping s, 3-CH3,
3ꢀ-CH3), 4.05 (3H, s, OCH3), 5.96, 6.03 (2H, both d, J 10.5,
H2, H2ꢀ isomer b and isomer a), 7.05, 7.10 (2H, both d, J 8.5,
H5, H5ꢀ isomer b and isomer a), 7.27 (1H, partially obscured
d, H7ꢀ), 7.56 (1H, br s, OH), 7.65–7.70 (3H, m, H1, H1ꢀ, OH),
7.94–8.04 (2H, m, H6, H6ꢀ), 8.17, 8.23 (1H, both d, J 8.5, H8ꢀ
isomer a and isomer b) [isomer a/isomer b ∼2.5/1]. m/z (FAB,
2,3,5-Trichloro-6-hydroxy-1,4-naphthoquinone[9] 28
trans-1-Methoxy-3-trimethylsilyloxybuta-1,3-diene[10]
20
(250 µL, 1.28 mmol) was added dropwise to a solution of p-
chloranil 27 (295 mg, 1.20 mmol) in dry toluene (30 mL) and
the mixture stirred overnight, after which the solvent was evap-
orated. The residue was dissolved in tetrahydrofuran (25 mL),
and concentrated aqueous hydrochloric acid (5 mL) added. The
mixture was heated under reflux for 20 min and then the mix-
ture allowed to cool. The mixture was then partitioned between
ethyl acetate (20 mL) and water (20 mL). The organic phase was
washed with water (3 × 20 mL), dried over sodium sulfate, and
evaporated under vacuum to give the crude 2,3,5-trichloro-6-
hydroxy-1,4-naphthoquinone[9] 28 as a red solid (226 mg, 68%)
whose spectroscopic data were in good agreement with those
reported[9] and which was used without purification.

Naphthoquinone Analogues of Conocurvone
783
PEG)734(M[37Cl] + H + 1, 21%), 733(M[37Cl] + 4H, 38), 732
(M[35Cl] + H + 1, 51), 731 (M[35Cl] + H, 71),
9-Acetoxy-8-(7ꢀ-(9ꢀ-acetoxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-5ꢀ,8ꢀ-
dioxo-5ꢀ,8ꢀ-dihydroquinolin-6ꢀ-yl)-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 36
8-Hydroxy-5-nitrosoquinoline Hydrochloride 33·HCl
A solution of 6,7-dibromoquinoline-5,8-dione 35 (494 mg,
1.6 mmol) and 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione 8 (806 mg, 3.1 mmol) in 1,2-dimethoxyethane
(35 mL) and diisopropylethylamine (1.6 mL, 9.4 mmol) was
heated under reflux for 4 h. After cooling to room temperature,
the mixture was poured into aqueous hydrochloric acid (1 M,
50 mL) and extracted with ethyl acetate (50 mL). The organic
extracts were washed with water (50 mL), dried over sodium
sulfate, and the volatiles were removed under vacuum.The resul-
tant residue was treated with acetic anhydride (5 mL), pyridine
(5 mL), and a catalytic amount of N,N-dimethylaminopyridine,
and the mixture stirred for 2 h. The mixture was then poured
into dichloromethane (100 mL) and aqueous acetic acid (1 M,
50 mL). The organic phase was separated, washed with water
(50 mL), dried over sodium sulfate, and evaporated under vac-
uum. The resultant residue was subjected to purification by
flash chromatography in dichloromethane/acetonitrile (9/1) to
afford the product (RF 0.4) as an orange/red film. Precip-
itation from dichloromethane/hexane gave an orange amor-
phous solid (257 mg, 22%), which was recrystallized from
ethyl acetate/hexane to give 9-acetoxy-8-(7ꢀ-(9ꢀ-acetoxy-3ꢀ,3ꢀ-
dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-
8ꢀ-yl)-5ꢀ,8ꢀ-dioxo-5ꢀ,8ꢀ-dihydroquinolin-6ꢀ-yl)-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 36 as red/orange microplates,
mp 192–195◦C. (Found: C 68.3, H 3.8, N 1.5. C43H29NO12
requires C 68.7, H 3.9, N 1.9%.) λmax/nm (ε/M−1 cm−1) 236
(66 070), 270sh (31 620), 370sh (6460), 456 (7410). νmax/cm−1
3600–3300wb, 2350w, 1800m, 1680m, 1660m, 1580m, 1570m.
δH 1.48, 1.49 (6H, 6H, s, s, 3-CH3, 3ꢀ-CH3), 2.12 (3H, s, OAc),
2.14 (3H, s, OAc), 5.91 (2H, d, J 10.5, H2 and H2ꢀ), 7.08 (2H, d,
J 8.5, H5 and H5ꢀ), 7.58 (2H, d, J 10.5, H1 and H1ꢀ), 7.74 (1H,
dd, J 8, 5, H3ꢀ), 7.94, 7.95 (2H, both d, J 8.5, H6 and H6ꢀ isomer
a and isomer b), 8.50 (1H, dd, J 8, 2, H4ꢀ), 9.12 (dd, J 5, 2, H2ꢀ)
[isomer a/isomer b ∼1/1]. m/z (FAB, 3NBA) 755 (M + H + 2,
58%), 754 (M + H + 1, 100), 752 (M + H, 22), 713 (29), 712
(45), 710 (16), 672 (17), 671 (44), 670 (80), 669 (57), 668 (64),
654 (25), 653 (25), 652 (43), 651 (29), 650 (19).
A solution of sodium nitrite (6.0 g, 87 mmol) in water (20 mL)
was slowly added, in small portions, to an ice-cooled stirred solu-
tion of 8-hydroxyquinoline 32 (11.6 g, 80 mmol) in concentrated
hydrochloric acid (15 mL), water (40 mL), and ice (40 g) over
2 h. During this time the reaction temperature was maintained
between 5 and 10◦C. The reaction mixture was then stirred at
0◦C overnight, the product filtered off, rinsed with cold water,
and finally dried under reduced pressure. This gave the crude
nitrosoquinoline[11] (contaminated with another compound) as
a yellow solid (14.9 g, 88%), which was used in the next reaction
without further purification. δH ([D6]DMSO) 6.98 (1H, d, J 10,
H7), 7.16 (1H, d, J 10, H6), 7.63 (1H, dd, J 8, 4.5, H3), 7.95 (1H,
dd, J 8, 1.5, H4), 8.67 (1H, dd, J 4.5, 1.5, H2).
8-Hydroxy-5-aminoquinoline 34
A solution of the nitrosoquinoline 33 (6.0 g, 28 mmol) in water
(24 mL) and aqueous sodium hydroxide (5 M, 40 mL) was
warmed to 40–45◦C, the oil bath removed, and sodium dithion-
ite (14.6 g, 84 mmol) added in small portions. After addition
was complete, nitrogen was bubbled through the reaction mix-
ture until it had cooled to 40◦C. The solution was then adjusted
to pH 7 with glacial acetic acid, the precipitate collected by fil-
tration, and dried to give the crude product as a dark solid (3.8 g,
83%). This crude material was suitable for use in the subse-
quent reaction. Recrystallization of the crude compound from
dichloromethane/hexane gave 8-hydroxy-5-aminoquinoline 34,
mp 139–141◦C (lit.[18] 142–143◦C). δH (90 MHz) 4.00–3.50
(2H, br s, NH2), 6.77 (1H, d, J 8, H6), 7.03 (1H, d, J 8, H7),
7.41 (1H, dd, J 8.5, 4.0, H3), 7.60–7.90 (1H, br s, OH), 8.22
(1H, dd, J 8.5, 1.5, H4), 8.77 (1H, dd, J 4.0, 1.5, H2). m/z (FAB,
3NBA) 161 (M + H + 1, 81%), 160 (M + H, 100).
6,7-Dibromoquinoline-5,8-dione 35
A solution of sodium bromate (3.64 g, 24 mmol) in water
(40 mL) was slowly added to a stirred solution of 8-hydroxy
5-aminoquinoline 34 (2.8 g, 18 mmol) in aqueous hydrobromic
acid (24%, 30 mL) and ethanol (95%, 30 mL) so that the tem-
perature was maintained below 50◦C. The reaction mixture was
warmed and stirred at 50◦C for 30 min and then poured into
ice water (300 mL). The crude product was collected by fil-
tration, rinsed with water, and dried. This material was then
taken up in hot ethyl acetate, filtered, and the filtrate evapo-
rated to give the dibromide 35 as a brown solid (2.38 g, 43%).
This material was suitable for use in subsequent reactions.
Recrystallization from dichloromethane/methanol gave 6,7-
dibromoquinoline-5,8-dione 35, mp 240–243◦C (dec.) (lit.[12]
245◦C). δH 7.83 (1H, dd, J 8.0, 4.5, H3), 8.61 (1H, d, J 8.0,
H4), 9.18 (1H, d, J 4.5, H2). δC ([CD3]2SO) 128.1 (CH), 135.2
(CH), 140.8 (Cq), 142.5 (Cq), 146.7 (Cq), 154.3 (CH), 174.2
(CO), 176.1 (CO). m/z (EI, 70 eV) 319 (M[81Br2], 15%), 317
(M[81Br79Br], 27), 315 (M[79Br2], 14), 238 (21), 236 (22), 210
(18), 208 (19), 184 (27), 182 (54), 180 (48), 133 (63), 131
(70), 105 (20), 102 (26), 101 (74), 100 (67), 78 (21), 77 (100).
m/z (ESI) 322 (M[81Br2] + H + 2, 37%), 320 (M[81Br2] + H
and M[81Br79Br] + H + 2, 80), 318 (M[81Br79Br] + H and
M[79Br2] + H + 2, 100), 316 (M[79Br2] + H, 40), 242 (8), 240
(12), 238 (7), 160 (7).
9-Hydroxy-8-(7ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-
7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-8ꢀ-yl)-5ꢀ,8ꢀ-
dioxo-5ꢀ,8ꢀ-dihydroquinolin-6ꢀ-yl)-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 37
A solution of aqueous lithium hydroxide monohydrate (8 mg
in 0.5 mL) was added to a solution of 9-acetoxy-8-(7ꢀ-(9ꢀ-
acetoxy-3ꢀ,3ꢀ-dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho
[2,1-b]pyran-8ꢀ-yl)-5ꢀ,8ꢀ-dioxo-5ꢀ,8ꢀ-dihydroquinolin-6ꢀ-yl)-3,3-
dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione 36 (15.2 mg) in
tetrahydrofuran (0.5 mL) and the mixture stirred overnight. The
reaction mixture was then diluted with aqueous hydrochloric
acid (2 mL, 1 M) and extracted with ethyl acetate (2 mL). The
extract was dried over sodium sulfate and concentrated under
vacuum. The residue was taken up in ethyl acetate and hex-
ane slowly added to afford 9-hydroxy-8-(7ꢀ-(9ꢀ-hydroxy-3ꢀ,3ꢀ-
dimethyl-7ꢀ,10ꢀ-dioxo-7ꢀ,10ꢀ-dihydro-3ꢀH-naphtho[2,1-b]pyran-
8ꢀ-yl)-5ꢀ,8ꢀ-dioxo-5ꢀ,8ꢀ-dihydroquinolin-6ꢀ-yl)-3,3-dimethyl-3H-
naphtho[2,1-b]pyran-7,10-dione 37 as a red precipitate (8.9 mg,
67%). δH 1.39, 1.42 (6H, 6H, s, s, 3-CH3, 3ꢀ-CH3), 6.09 (2H,
d, 10.5, H2 and H2ꢀ), 7.09, 7.17 (2H, both d, 8.5, H5 and H5ꢀ

784
I. T. Crosby et al.
isomer b and isomer a), 7.54 (2H, d, 10.5, H1 and H1ꢀ), 7.67,
7.79 (2H, both d, H6 and H6ꢀ isomer b and isomer a), 7.92 (1H,
dd, 8, 4.5, H3ꢀ), 8.46 (1H, d, 8, H4ꢀ), 9.10 (1H, d, 4.5, H2ꢀ). m/z
(FAB, 3NBA) 670 (M + H + 2, 18%), 668 (M + H, 15).
(5 mL) and diisopropylethylamine (130 µL, 0.72 mmol) was
heated at reflux under nitrogen for 2.5 h. After cooling to ambi-
ent temperature, pyridine (1 mL) and acetic anhydride (1 mL)
were added, and stirring maintained for 1.5 h. The mixture was
then poured into dichloromethane (20 mL) and aqueous acetic
acid (1 M, 20 mL), the organic phase separated, washed with
water (20 mL), dried over sodium sulfate, and the volatiles were
removed under vacuum.The residue was subjected to flash chro-
matographyindichloromethane/acetonitrile(95/5)andthecrude
diacetate (RF 0.75) was obtained as an orange/red film (18.6 mg,
20%), which was precipitated from dichloromethane/hexane to
give 41 as an orange amorphous solid, mp 192–195◦C. (Found:
[M + H + 2]+ (FAB, 3NBA) 754.187. C43H32NO12 requires
754.192.) λmax/nm (ε/M−1 cm−1) 234 (30 200), 270sh (12 880),
450 (1170). νmax/cm−1 3750–3200mb, 3050w, 3000w, 1810s,
1700s, 1620w, 1590w. δH 1.48 (s, 2 × CH3), 1.50 (s, 2 × CH3),
2.13 (s, CH3CO), 2.14 (s, CH3CO), 5.92 (d, J 10.5, H2 and H2ꢀ),
7.11 (d, J 8.5, H5 and H5ꢀ), 7.59 (d, J 10.5, H1 and H1ꢀ), 7.96
(dd, J 8.5, 5.5, H4ꢀ, H6, and H6ꢀ), 9.15 (br s, H3ꢀ), 9.46 (br s,
H1ꢀ). m/z (FAB, 3NBA) 755 (M + H + 3, 52%), 754 (M + H + 2,
100), 753 (M + H + 1, 50), 752 (M + H, 51), 712 (27), 711 (19),
710 (29), 671 (29), 670 (59), 669 (52), 668 (83), 667 (24), 654
(25), 653 (22), 652 (48), 651 (29), 650 (28), 636 (18).
Isoquinoline-5,8-dione 39
A solution of 5-hydroxyisoquinoline 38 (0.5 g, 3.4 mmol) in
methanol (50 mL) was added dropwise over ∼40 min to a stirred
solution of potassium nitrodisulfonate (Fremy’s salt, 2.3 g) in
water (120 mL) and aqueous potassium dihydrogen phosphate
(0.17 M, 35 mL). After addition was complete the mixture
was extracted with dichloromethane (2 × 50 mL), the extracts
washed with water (2 × 100 mL), dried over sodium sulfate, fil-
tered through a plug of neutral alumina, and the solvent removed
under vacuum.This gave a yellow solid (245.3 mg, 45%) that was
purified by flash chromatography in methanol/dichloromethane
(5/95) to give isoquinoline-5,8-dione 39, mp 133–137◦C (lit.[13]
135◦C). δH 7.03 (1H, d, J 10.5, H7 or H6), 7.09 (1H, d, J 10.5,
H7 or H6), 7.87 (1H, dd, J 4.5, 0.5, H4), 9.09 (1H, d, J 4.5, H3),
9.36 (1H, br s, H1). m/z (EI, 70 eV) 159 (M, 100%), 131 (26),
105 (54), 103 (36), 77 (28), 76 (23), 50 (60). m/z (FAB, 3NBA)
163 (M + H + 3, 15%), 162 (M + H + 2, 100), 161 (M + H + 1,
47), 160 (M + H, 23), 149 (57).
6,7-Dibromoisoquinoline-5,8-dione 40
References
A solution of isoquinoline-5,8-dione 39 (245 mg, 1.5 mmol) in
dichloromethane (5 mL) was added to a solution of sodium
dithionite (0.6 g) in water (10 mL). The precipitated orange 5,8-
dihydroxyisoquinoline was collected by filtration, washed with
water, dried, and used immediately. δH ([D6]DMSO) 6.78 (1H,
d, J 8.5, H7 or H6), 6.91 (1H, d, J 8.5, H7 or H6), 7.81 (1H, d, J
5.5, H4), 8.41 (1H, br s, H3), 9.36 (1H, br s, H1), 9.56 (1H, br s,
OH), 9.83 (1H, br s, OH). m/z (FAB, 3NBA) 185 (M + Na + 1,
27%), 163 (M + H + 1, 17), 162 (M + H, 100), 161 (25).
A solution of sodium bromate (284 mg) in water (2 mL)
was added dropwise to a stirred suspension of the aforemen-
tioned quinol in aqueous hydrobromic acid (24%, 4 mL) and
ethanol (95%, 4 mL). After addition was complete the solu-
tion was warmed at 55◦C for 40 min and then poured onto
ice-water. The resulting precipitate was collected by filtration,
dried, and purified by flash chromatography in hexane/ethyl
acetate (2/1). The band at RF 0.3 (58 mg, 12%) was recrystal-
lized from methanol to give 6,7-dibromoisoquinoline-5,8-dione
40 as a golden amorphous solid, mp 210–212◦C. (Found: C 33.9,
H 0.9, N 4.3. C9H3Br2NO2 requires C 34.1, H 1.0, N 4.4%.)
λmax/nm (ε/M−1 cm−1) 238 (13 180), 263 (8710), 322 (1480).
νmax/cm−1 3700–3300m br, 1700s, 1600m, 1560w, 1550m.
δH 7.99 (1H, d, J 6, H4), 9.12 (1H, J 6, H3), 9.45 (1H, s,
H1). m/z (EI, 70 eV) 319 (M[81Br2], 53%), 317 (M[81Br79Br],
100), 0.315 (M[79Br2], 56), 238 (77), 236 (78), 210 (27), 208
(25), 182 (31), 180 (31), 155 (14), 153 (17), 133 (26), 131
(30). (ESI) 322 (M[81Br2] + H + 2, 30%), 320 (M[81Br2] + H
and M[81Br79Br] + H + 2, 90), 318 (M[81Br79Br] + H and
M[79Br2] + H + 2, 100), 316 (M[79Br2] + H, 37), 242 (13), 240
(18), 238 (10), 143 (37), 142 (22).
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A solution of 6,7-dibromoisoquinoline-5,8-dione 40 (38.9 mg,
0.12 mmol) and 9-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]
pyran-7,10-dione 8 (63 mg, 0.25 mmol) in 1,2-dimethoxyethane