Total synthesis of monosporascone and dihydromonosporascone

Article abstract of DOI:10.1039/c4ob00331d

The first total synthesis of monosporascone is presented. The five-step synthesis developed includes a silver acetylide-acid chloride coupling, domino Diels-Alder-retro-Diels-Alder reaction, and an intramolecular Friedel-Crafts acylation, and provides the natural product in 57% yield overall. Selective reduction of monosporascone also afforded the related metabolite dihydromonosporascone. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00331d

Organic &
Biomolecular Chemistry
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Total synthesis of monosporascone and
dihydromonosporascone†
Cite this: Org. Biomol. Chem., 2014,
12, 2801
Kathryn A. Punch and Matthew J. Piggott*
Received 13th February 2014,
Accepted 16th March 2014
The first total synthesis of monosporascone is presented. The five-step synthesis developed includes a
silver acetylide-acid chloride coupling, domino Diels–Alder-retro-Diels–Alder reaction, and an intramole-
cular Friedel–Crafts acylation, and provides the natural product in 57% yield overall. Selective reduction of
monosporascone also afforded the related metabolite dihydromonosporascone.
DOI: 10.1039/c4ob00331d
www.rsc.org/obc
cin B (2);7 a sequence involving consecutive [2 + 2 + 2] alkyne
cyclotrimerisation, Ullman, Claisen, and ring-closing meta-
Introduction
The naphtho[2,3-c]furandiones (isofuranonaphthoquinones) thesis reactions; and, in the synthesis of 1, key Friedel–Crafts
comprise a relatively small group of secondary metabolites, reactions.8 Tsunoda and co-workers recently completed an
with a wide variety of biological activities, isolated from efficient total synthesis of the cytotoxic aphid pigment furana-
fungal, botanical, bacterial and insect sources. In 2005, when phin (3), in a total of eight steps and 23% yield, using a key
this class of compounds was comprehensively reviewed,1 there boron trifluoride-acetic acid-mediated Fries rearrangement.9
were 17 natural products possessing the isofuranonaphthoqui-
In a continuation of our interest in naphtho[2,3-c]furan-
none ring-system, and a similar number of partially reduced diones and related compounds,1,10–14 we targeted monosporas-
congeners. Since that time a single new member has been dis- cone (4) for total synthesis (Scheme 1). Monosporascone and
covered: 1 (Fig. 1), which is moderately cytotoxic to a range its dihydro derivative 5 were first isolated from the fungus
of cancer cell lines and non-malignant human foreskin
fibroblasts.2
Isofuranonaphthoquinones continue to attract the atten-
tion of synthetic chemists, with recent syntheses making use
of silver(II) and manganese(III)-mediated radical cyclisation
of 1,4-naphthoquinone derivatives;3–5 a double conjugate
addition of a hydroxymethyldihydronaphthoquinone mono-
ketal to propiolate esters;6 oxidative skeletal rearrangement of
a naphtho[1,2-b]furan-5-ol, applied to the synthesis of bhimamy-
Fig. 1 Recently synthesised isofuranonaphthoquinone (1, 2) and related
(3) natural products.
School of Chemistry and Biochemistry, The University of Western Australia, Perth,
Scheme 1 Monosporascone (4) could be
a synthetic precursor to
WA, Australia. E-mail: matthew.piggott@uwa.edu.au; Fax: +618 6488 1005;
Tel: +618 6488 3170
related natural products 5,15 6,16 7,16 816–18 and 9.17,18 Monosporascol A
(6) is optically active, and presumably homochiral, but its configuration
has not been determined.16
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of new compounds. See DOI: 10.1039/c4ob00331d
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Gelasinospora pseudoreticulata, and hence originally named
GP-A and GP-B, respectively.15 Both compounds were shown to
inhibit the pharmacotherapeutically important enzyme mono-
amine oxidase. Monosporascone (4) was named after the
fungus it was subsequently isolated from – Monosporascus
cannonballus16 – the causative agent of root rot and vine
decline in commercial melon species.
Monosporascone is the only known isofuranonaphthoqui-
none with oxygenation only at the 5- and 7-positions, and thus
presents a unique synthetic challenge. In addition, there are a
number of related biologically active metabolites with the
same substitution pattern that could conceivably be derived
from monosporascone (Scheme 1), in some cases very suc-
cinctly. These considerations were the impetus behind the
work described herein.
Scheme 3 Failed and revised approaches to monosporascone (4). X =
OMe, OH or Cl.
vated 4-position of 13 proceeds as expected to give 18
(Scheme 3). This is supported by the reaction of 13 with
3-furoyl chloride (15), which in the presence of SnCl4 gave 16
in excellent yield (Scheme 2). The site for subsequent cyclisa-
tion in 18, however, is now strongly deactivated to electrophilic
aromatic substitution by the ortho-carbonyl and further
(weakly) deactivated by the two meta-methoxy groups. As a
result cyclisation does not occur and side reactions ensue.
With SnCl4 as the Lewis acid, it is more difficult to explain
why 15 reacts cleanly while 11 does not react at all. However,
1,4-dimethoxybenzene (10) was also unreactive with 11 under
these conditions.
Results and discussion
The initial approach to monosporascone was based on our pre-
vious synthesis of the 5,8-dihydroxy analogue 12 (Scheme 2).
In that instance the double Friedel–Crafts acylation of hydro-
quinone dimethyl ether (10) with furan-3,4-dicarbonyl chloride
(11),19 with concomitant demethylation, provided 12 cleanly
and in excellent yield.10 Application of this methodology to
resorcinol dimethyl ether (13) gave complex mixtures with
AlCl3 and no reaction with SnCl4, with no sign of monosporas-
cone (4) or its methyl ether 14 detected in any attempt. With
AlCl3 at least, presumably the first acylation at the doubly-acti-
In any case, the failure of this initial foray required a
rethink. Since it appeared that cyclisation of putative inter-
mediate 18 was not possible, we chose to investigate the
reverse approach, where the initial event in the construction of
the central ring was bond formation at C5 of resorcinol
dimethyl ether (or a derivative), allowing cyclisation onto the
position activated by both ortho and para methoxy groups
(Scheme 3 right). Although the precedent in Scheme 2
suggested that this approach should work from ketone 19, in
parallel we also pursued the variant in which the furan is teth-
ered by an activating alkyl bridge, as in 20; that is, via the
naphtho[2,3-c]furan-4(9H)-one, with the view to install the car-
bonyl group20 of monosporascone at a later stage.
Approach 1: via a diarylmethane (33)
Our first approaches to monosporascone (see also the next
section) sought to take advantage of available dimethyl furan-
3,4-dicarboxylate (21) (Scheme 4), the precursor to acid chlor-
ide 11. Thus, 21 was mono-saponified and chemoselective
reduction of the carboxylic acid 22 with borane–dimethyl
sulfide afforded the known primary alcohol 23,21 which was
also previously made in low yield by direct partial reduction of
the diester 21 with DIBAL.22 Swern oxidation, as reported,22
then provided the required ‘semialdehyde’ 24. Addition of the
aryllithium 25 generated from 1-bromo-3,5-dimethoxybenzene
to this aldehyde gave the expected carbinol 26 in rather dis-
appointing yield.
Scheme 2 Reagents and conditions: (a) AlCl3, DCE (1,2-dichloro-
ethane); (b) SnCl4, DCM.
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Scheme 4 Reagents and conditions: (a) 1. NaOH, MeOH, 2. H3O+; (b)*
H3B–SMe2, THF; (c) DMSO, (COCl)2, DCM; (d) 1. 3,5-dimethoxybromo-
benzene, BuLi, THF, 2. 24. Literature yields are shown in brackets. *The
reported procedure used H3B–THF.21 #We attribute no significance to
the lower yield in our hands; the reaction was carried out only once.
Although the final step in Scheme 4 could almost certainly
have been improved with further experimentation, the rather
onerous synthesis of aldehyde 24 (six steps from furan and
dimethyl acetylenedicarboxylate) led us to explore a more
efficient route (Scheme 5).
Low temperature addition13 of the lithium acetylide gener-
ated from ethyl propiolate (27) to 3,5-dimethoxybenzaldehyde
(28) gave the expected secondary alcohol 29, which underwent
a
domino Diels–Alder-retro-Diels–Alder reaction13,23 with
4-phenyloxazole (30)24 providing the 3,4-disubstituted furan
31. Lewis or Brønsted acid-catalysed Friedel–Crafts ring
closure at this juncture could, in principle, provide access
to monosporascone (4) via racemic monosporascol A (6)
(Scheme 1); however, we expected the benzylic alcohol to be
incompatible with such conditions, and as such this was not
Scheme 5 Reagents and conditions: (a) 1. BuLi, THF, −100 °C, 2. 28; (b)
hydroquinone, 200 °C; (c) TMSCl, NaI, MeCN; (d) 1. NaOH, MeOH,
attempted. Instead 31 was deoxygenated with trimethylsilyl 2. H3O+; (e) (COCl)2, 0 °C (crude yield indicated); (f) AlCl3, DCE, 0 °C or
iodide,13,25 affording the diarylmethane 32 in excellent yield.
SnCl4, PhH, 0 °C; (g) 1. PCl5, PhH, reflux, 2. SnCl4, 0 °C.
Saponification then provided the carboxylic acid 33 quantitat-
ively after acidification. Attempts to generate the corres-
ponding acid chloride 34 with thionyl chloride led to complete
degradation, even at low temperature. The reaction was
proportionation. The regioidentity of 36 was established by a
1D NOESY experiment: irradiation of H6 led to enhancements
in the signals for both methoxy groups. The results described
successful with oxalyl chloride, however, and the acid chloride
above suggest that chlorination, either before or after ring
34 was surprisingly stable, not hydrolysing during TLC, for
closure, is required to stabilise the product under the reaction
conditions.
Our other endeavours (carried out in parallel) had born
fruit at this time so, while it is probably possible to elaborate
36 to monosporascone through judicious redox transfor-
mations, we made no attempt at this task.
example.
1
Based on the H NMR spectrum of the crude product, the
attempted intramolecular Friedel–Crafts acylation of 34
with AlCl3 gave primarily what appeared to be a dialdehyde
(although this was not properly identified), presumably arising
from ring-opening of the furan. Surprisingly, based on pre-
cedent,13 the use of the milder Lewis acid SnCl4 with the iso-
Approach 2: via a diarylketone (37)
lated acid chloride 34 led to complete degradation, with no 35
detected. When this reaction was repeated with acid chloride
generated in situ using PCl5, cyclisation was successful, but
accompanied by chlorination of the benzene ring, as apparent
from the mass spectrum of the product 36. Presumably the
chlorinating agent is PCl5, or perhaps Cl2 arising from its dis-
Our first venture in this area mirrored the approach outlined
in Scheme 4. Addition of one equivalent of aryllithium 25 to
diester 21 did give the desired ketone 37, but only in low yield
and, not unexpectedly, accompanied by the corresponding
tertiary alcohol arising from double addition (Scheme 6). An
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Scheme 7 Reaction of 29 with MnO2 gave the unexpected tautomeri-
sation product 44.
structure, 41 was reacted with N-methylbenzylamine; indeed
this gave rise to the expected amide 42.
The reaction of organocuprate 39 with anhydride 41 did
provide the desired keto-acid 38, but unfortunately in no
better yield than the aryllithium/ester substitution reaction
(step a). Once again, the problems associated with monosub-
stitution of a furan-3,4-dicarboxylic acid derivative led us to
consider an alternative approach in which the furan ring is
constructed later in the synthesis. Specifically, we hoped to
capitalise on the success of the successful cycloaddition–
cycloreversion described in Scheme 5 but with the even better
dienophile, keto-ester 43 (Scheme 7).
Scheme 6 Reagents and conditions: (a) THF, −78 °C → RT (product is
37); (b) LiOH, MeOH–H2O, 0 °C; (c) CuCN·2LiCl, THF, −78 → −40 °C,
*The structure of such organocuprates is poorly understood; (d) THF,
−78 °C → RT, 2. H3O+ (product is 38); (e)19 1. 20% NaOH, reflux, 2. H3O+;
(f) Ac2O, reflux; (g) xs BnNHMe, DCM.
attempt to saponify the ester under standard conditions
(NaOH, heat) lead to ring-opening of the furan, as apparent
1
from the absence of relevant signals in the H NMR spectrum
Since we had 29 in hand, the first synthesis of 43 was by oxi-
dation of the benzylic/propargylic alcohol with MnO2. To our
surprise, the major product of this reaction was not that of oxi-
dation, but tautomerisation – the alkene 44. The cis-configur-
ation of the product 44 is based on comparisons of the vicinal
coupling constant of similar compounds in the literature. In
isolation the value for 44 is equivocal at 12 Hz, but comparable
to that for the phenyl ketone 45 (11.7 Hz)28 and very different
from the trans-isomer 46 (15.5 Hz).29 Such cis-selective “redox
isomerisation” has been reported previously using sodium car-
bonate as catalyst,30 and presumably the slightly basic MnO2 is
responsible for this side-reaction in the current work. Indeed,
when the MnO2 was pre-washed with acid the formation of
alkene 44 was diminished, but not completely avoided. The
desired ynone 43 was also found to be light sensitive, decom-
posing under ambient conditions and complicating separation
from the alkene. Fortunately a more direct and efficient syn-
thesis31 was achieved by the reaction of silver acetylide 4832
with acid chloride 4733 (Scheme 8), affording an excellent yield
of 43, which was used promptly in the next step.
of the crude product. The proclivity of isofuranonaphthoqui-
nones to conjugate addition at the furan α-positions has
been noted previously,10 and presumably extends to other
furans with electron-withdrawing groups at the β-positions.
Fortunately, under milder conditions (LiOH, 0 °C), competing
ring-opening was avoided, providing the carboxylic acid 38 in
good yield after acidification.
An attempt was made to improve on the yield of the key
carbonyl substitution reaction by use of an organocuprate
intermediary 39, generated by transmetallation of aryllithium
25 with CuCN/2LiCl.26 However, reaction of one equivalent of
39 with bis-acid chloride 11, followed by hydrolytic workup,
failed to provide any of the expected keto-acid 38, nor any
other identifiable product.
We also investigated the analogous reaction of novel bicyclic
anhydride 41, which, unlike the acid chloride 11, can only
undergo mono-substitution with an organocuprate. Anhydride
41 was prepared by dehydrative cyclisation of furan-3,4-dicar-
boxylic acid (40).19 Whilst 41 passed elemental analysis, and
the spectroscopic data supported the cyclic anhydride struc-
ture (e.g., an IR absorption at 1780 cm–1), we were initially
thrown by the upfield 13C NMR chemical shift of the carbonyl
carbons (155.2 ppm). However, the carbonyl carbons of
other strained anhydrides resonate at similar frequencies
(e.g. malonic anhydride: 160.3 ppm27), and the mesomeric
effect of the furan oxygen would be expected to further shield
the carbonyl carbons in 41. Nevertheless, to help confirm the
As expected, the Diels–Alder-retro-Diels–Alder reaction of 43
with 4-phenyloxazole 30 proceeded at considerably lower temp-
erature than that required for the less electron deficient dieno-
phile 29 (see Scheme 5), giving furan 49 in excellent yield
(Scheme 8).
Attempts to cyclise ester 49 directly with Eaton’s reagent34
or polyphosphoric acid (PPA)35 led to no reaction or decompo-
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As proof of concept that monosporascone can be a synthetic
precursor to the related natural products depicted in
Scheme 1, 4 was subjected to reduction with zinc in acetic
acid,39 providing dihydromonosporascone (5) in modest (but
unoptimised) yield. The 1H NMR spectrum of this material
also matched the data reported for the natural product.15
Conclusions
The first total synthesis of the isofuranonaphthoquinone
natural product monosporascone (4) has been achieved in five
linear steps and an overall yield of 57%, via a sequence of
silver acetylide acylation, cycloaddition–cycloreversion and
Friedel–Crafts acylation reactions. The brevity and efficiency of
this route can provide quantities of monosporascone sufficient
for further biological evaluation, and also elaboration to
several biologically active natural products bearing the same
framework and substitution pattern, as exemplified by the syn-
thesis of dihydromonosporascone in one extra step.
Experimental
General details
Benzene, 1,2-dichloroethane (DCE) and dichloromethane
(DCM) were distilled from CaH2; tetrahydrofuran (THF) and
toluene were distilled from sodium benzophenone ketyl (all
under inert gas). Acetonitrile was dried over activated 3A sieves
overnight. RSF = rapid silica filtration.26
1H and 13C nuclear magnetic resonance (NMR) spectra were
obtained using Bruker AM-300 (300 MHz for 1H and 75.5 MHz
for 13C), Varian Gemini-400 (400 MHz, 1H, 100 MHz, 13C),
Bruker AV500 (500 MHz, 1H, 125.8 MHz, 13C) and Bruker
AV600 (600 MHz, 1H, 150.9 MHz, 13C) spectrometers. Chemical
shifts are expressed in ppm relative to CHCl3 (1H, δ 7.26),
CDCl3 (13C, δ 77.16), D3CSOCD2H (1H, δ 2.50), (D3C)2SO (13C, δ
39.50), D3CCOCD2H (1H, δ 2.05), (D3C)2CO (13C, δ 29.84), as
appropriate; J values are given in hertz (Hz). Routine assign-
ments of 13C signals were made with the assistance of
DEPT-135 and DEPT-90 experiments and full assignments of
1H and 13C signals were derived from HSQC and 1D and 2D
NOESY experiments performed on either the Bruker AV500 or
the Bruker AV600 spectrometers.
Scheme 8 Reagents and conditions: (a) PhMe, 90 °C; (b) PhMe, reflux;
(c) PPA 100 °C (n.r.), 140 °C (dec.); Eaton’s reagent, 50 °C (n.r.); (d) LiOH,
MeOH, H2O, 0 °C; (e) 1. PCl5, PhH, reflux, 2. SnCl4, 0 °C; (f) SOCl2; (g)
AlCl3, DCE.
sition at higher temperatures. Saponification of 49 provided
the carboxylic acid 38, but this was also unreactive with PPA36
and Eaton’s reagent, and partially decomposed with concen-
trated sulfuric acid.37 Similarly, no cyclisation occurred in
refluxing trifluoroacetic anhydride.38 When the acid chloride
50 generated in situ using PCl5 was treated with SnCl4,13 only a
trace of monosporascone methyl ether (14) was isolated, the
1
Mass spectra were recorded on a VG Autospec instrument
using electron ionisation (EI+) or on a Waters GCT Premier
Instrument with an Agilent 7890A GC using chemical ioniza-
tion (CI, methane) and an Agilent DB-5MS column. Other
general details are as reported previously.40
major product appearing (based on the H NMR spectrum) to
result from ring-opening of the furan. In direct contrast to the
earlier observations with 33/34 (Scheme 5), reaction of 38 with
oxalyl chloride resulted in multiple products but, with neat
thionyl chloride, quantitatively provided the acid chloride 50,
which was stable enough to be fully characterised. To our great
delight, treatment of this isolated acid chloride 50 with five
equivalents of AlCl3,12 with an extended reaction period to
allow selective demethylation of the peri methoxy group, then
afforded monosporascone (4) in good yield. The NMR spectra
of the synthetic product were virtually identical with those
reported for the naturally-derived material.15
3-(2,4-Dimethoxybenzoyl)furan (16)
SnCl4 (63 µL, 0.50 mmol) was added to a stirred solution of
1,3-dimethoxybenzene (13) (42 mg, 0.30 mmol) and 3-furoyl
chloride (15) (40 mg 0.31 mmol) in anhydrous DCE (10 mL)
under argon at 0 °C, whereupon the colourless solution slowly
turned red. After 1 h the reaction mixture was allowed to warm
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to room temperature and stirred for a further 4 h. The red solu- mixture was allowed to warm to room temperature over 6.5 h
tion was diluted with ice-cold 2 M HCl (75 mL), saturated with and then quenched with AcOH (5 mL). The orange solution
oxalic acid and stirred for 30 min. The resulting purple was partitioned between ether (200 mL) and saturated
mixture was extracted with EtOAc (3 × 60 mL). The extract was NaHCO3 (100 mL). The ether extract was washed with saturated
washed with saturated aqueous NaHCO3 (50 mL) and brine NaHCO3 (2 × 50 mL), H2O (50 mL) and brine (50 mL) then
(50 mL), dried and evaporated to yield a pale red oil (90 mg), dried and evaporated to give a brown oil, which was subjected
which was subjected to rapid silica filtration. Elution with to RSF. Elution with EtOAc–hexanes (1 : 4) gave 29 as a yellow-
EtOAc–hexanes (1 : 9) gave 16 as a pale orange oil (70 mg, orange solid (5.19 g, 56%), which crystallised from hexanes as
98%). On a larger scale (10 mmol) the yield was lower (68%). a pale yellow solid, m.p. = 41–43 °C. Rf (EtOAc–hexanes 1 : 9)
Kugelrohr distillation (230° at 2 mm Hg) of a sample gave a 0.2; IR νmax cm−1: br 3438 (OH), 2236 (CuC), 1711 (CvO);
pale yellow oil. Rf (1 : 9 EtOAc–hexanes): 0.15. IR (thin film) 1H NMR (400 MHz, CDCl3) δ 6.67 (dd, J2′/6′,4′ = 2.0 Hz, J2′/6′,4
=
νmax cm–1: 1650 (CvO). H NMR (300 MHz) δ 7.78 (dd, J = 1.5, 0.4 Hz, 2H, H2′/6′), 6.44 (t, J4′,2′/6′ = 2 Hz, 1H, H4′), 5.50 (br
0.8 Hz, 1H, H2); 7.45–7.41 (m, 2H, H5/H6′); 6.82 (dd, J = 2.0, d, J4,OH = 6.4 Hz, 1H, H4), 4.24 (q, J = 7.2 Hz, 2H, OCH2), 3.80
0.8 Hz, 1H, H4); 6.53–6.49 (m, 2H, H5′/H3′); 3.86 (s, 3H, (s, 6H, 2 × OCH3), 2.48 (br d, JOH,4 = 6.4 Hz, 1H, OH), 1.31 (t,
OCH3); 3.79 (s, 3H, OCH3). 13C NMR (75.5 MHz) δ 188.3 (CO); J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 161.3
163.1 (ArO), 159.1 (ArO); 149.0 (C2); 143.6 (C5); 131.4 (C4); (CvO), 153.4 (C3′/5′), 140.9 (C1′), 104.7 (C2′/6′), 101.0 (C4′),
128.4; 122.4; 109.8 (ArH); 104.2 (ArH); 98.9 (C3′), 55.6 (CH3O); 85.9 (C3), 70.0 (C2), 64.5 (C4), 62.4 (OCH2), 55.6 (OCH3), 14.1
55.5 (CH3O). MS (EI) m/z 232 (M•+, 69%), 215 (39), 203 (100), (CH3); MS (EI) m/z 264 (M•+, 100%), 191 (77), 166 (96), 165 (63);
1
•+
•+
165 (41), 95 (47); HRMS observed: 232.0740, C13H12O4
requires: 232.0736.
HRMS found: 264.0997; C14H16O5 requires: 264.0998; Micro-
analysis found: C 63.7, H 6.0%; calculated for C14H16O5: C 63.6,
H 6.1%.
Methyl 4-[(3,5-dimethoxyphenyl)(hydroxy)methyl]-3-furoate
(26)
Ethyl 4-((3,5-dimethoxyphenyl)(hydroxy)methyl)-3-furoate (31)
A 1.1 M solution of BuLi in hexane (0.60 mL, 0.68 mmol) was Hydroquinone (5 mg) was added to a molten mixture of 29
added to a stirred solution of 1-bromo-3,5-dimethoxybenzene (1.09 g, 4.12 mmol) and 30 (3.1 g, 21 mmol) under argon and
(146 mg, 0.670 mmol) in THF (2.5 mL) at 0 °C under argon. the reaction mixture was heated at 200 °C for 90 min. TLC
After stirring for 30 min, the solution of the aryllithium 25 was (EtOAc–hexanes 1 : 4) after this time showed no detectable
added dropwise to methyl 4-formyl-3-furoate (24)22 (105 mg, starting material 29. After cooling, the brown residue was sub-
0.680 mmol) in THF (4.5 mL) at –78 °C. The reaction mixture jected to RSF. Elution with EtOAc–hexanes 1 : 19 gave excess
was allowed to warm to room temperature overnight, during 4-phenyloxazole. Further elution with EtOAc–hexanes 1 : 4 gave
which time the solution turned orange, then quenched with 31 as a pale yellow oil (891 mg, 71%). Rf (EtOAc–hexanes 1 : 4)
saturated NH4Cl (5 mL) and extracted with ether (3 × 50 mL). 0.3; IR νmax cm−1: br 3700–3200 (OH), 1715 (CvO); 1H NMR
The extract was washed with water (40 mL), dried and evapor- (400 MHz, CDCl3) δ 7.99 (d, J2,5 = 1.6 Hz, 1H, H2), 7.00 (dd, J5,2
ated to yield a yellow oil (126 mg), which was subjected to RSF. = 1.6 Hz, J5,CHOH = 0.8 Hz, 1H, H5), 6.60 (d, J2′/6′,4′ = 2.4 Hz, 2H,
Elution with EtOAc–hexanes (1 : 9) gave the 26 as a pale orange H2′/6′), 6.40 (t, J4′,2′/6′ = 2.4 Hz, 1H, H4′), 5.82 (d, JCH,OH
=
oil (34 mg, 21%). Rf (1 : 4 EtOAc–hexanes): 0.15. IR (thin film) 5.2 Hz, 1H, CHOH), 4.89 (d, JOH,CH = 5.2 Hz, 1H, OH), 4.32
νmax cm−1: 3431 br (OH), 1724 (CvO). 1H NMR (300 MHz) (m, 2H, OCH2), 3.78 (s, 6H, 2 × OCH3), 1.34 (t, J = 7.2 Hz, 3H,
δ 7.98 (d, J = 1.7 Hz, 1H, H2), 7.01 (dd, J = 1.7, 0.9 Hz, 1H, H5), CH3); 13C NMR (100 MHz, CDCl3) δ 165.0 (CvO), 160.8 (C3′/
6.59 (d, J = 2.3 Hz, 2H, H2′/H6′), 6.39 (t, J = 2.3 Hz, 1H, H4′), 5′), 149.9 (C2), 144.1 (C1′), 142.3 (C5), 129.0 (C3), 117.9 (C4),
5.83 (sl. br s, 1H, CHOH), 4.85 (br s, 1H, OH), 3.85 (s, 3H, 104.6 (C2′/C6′), 99.9 (C4′), 67.7 (CHOH), 61.3 (CH2O), 55.5
CO2CH3), 3.78 (s, 6H, OCH3). 13C NMR (75.5 MHz) δ 165.3 (CH3O), 14.3 (CH3); MS (EI) m/z 306 (M•+, 41%), 205 (28), 149
•+
(CvO); 160.8 (ArO); 149.9 (C2); 144.1 (C1′); 142.3 (C5); 128.9 (46), 139 (100); HRMS found: 306.1105; C16H18O6 requires:
(C3), 117.5 (C4), 104.5 (C2′/C6′), 99.2 (C4′), 67.7 (CHOH), 55.5 306.1103.
(OCH3), 52.2 (CO2CH3). MS (EI) m/z 292 (M•+, 40%), 276 (19),
•+ Ethyl 4-(3,5-dimethoxybenzyl)-3-furoate (32)
139 (100), 123 (28); HRMS found: 292.0944; C15H16O6
requires: 292.0947.
TMSCl (1.54 mL, 12.2 mmol) was added to a solution of NaI
(1.82 g, 12.2 mmol) in anhydrous MeCN (15 mL) under argon.
The resulting yellow suspension was treated with a solution of
Ethyl 4-(3,5-dimethoxyphenyl)-4-hydroxybut-2-ynoate (29)
A
1.55 M solution of BuLi in cyclohexane (24.7 mL, 31 (625 mg, 2.04 mmol) in anhydrous MeCN (35 mL), where-
38.5 mmol) was added dropwise to a stirred solution of ethyl upon a dark red solution formed immediately. After 10 min
propiolate (4.1 g, 42 mmol) in anhydrous THF (80 mL) under the reaction mixture was diluted with H2O (100 mL) and
argon at −100 °C. The solution was warmed to −80 °C over extracted with ether (4
× 30 mL). The organic extract
30 min, then cooled again to −100 °C. The solution of lithium was washed with 5% aqueous sodium thiosulfate solution
ethoxycarbonylacetylide thus formed was treated dropwise via (2 × 50 mL) and brine (50 mL), dried and evaporated to give 32
cannula with a −40 °C solution of 3,5-dimethoxybenzaldehyde as a pale yellow oil (487 mg, 82%), which required no further
1
(28) (5.8 g, 35 mmol) in anhydrous THF (60 mL). The reaction purification. Rf (EtOAc–hexanes 1 : 4) 0.6; H NMR (400 MHz,
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CDCl3) δ 7.98 (d, J2,5 = 1.6 Hz, 1H, H2), 7.06 (m, 1H, H5), 6.40 benzene (3 mL) at 0 °C under argon. The reaction mixture was
(d, J2′/6′,4′ = 2.0 Hz, 2H, H2′/6′), 6.32 (t, J4′,2′/6′ = 2.0 Hz, 1H, allowed to warm to room temperature and then heated under
H4′), 4.26 (q, J = 7.2 Hz, 2H, OCH2), 3.94 (br s, 2H, CH2), 3.76 reflux for 1 h. After cooling to room temperature, the reaction
(s, 6H, 2 × OCH3), 1.30 (t, J = 7.2 Hz, 3H, CH3); 13C NMR mixture was added dropwise to a stirred solution of SnCl4
(100 MHz, CDCl3) δ 163.6 (CvO), 160.9 (C3′/5′), 149.1 (C2), (87 μL, 0.75 mmol) in anhydrous benzene (3 mL) at 0 °C,
142.3 (C1′), 142.1 (C5), 124.7 (C3), 118.5 (C4), 107.0 (C2′/C6′), whereupon an orange solution formed immediately. The reac-
98.3 (C4′), 60.3 (OCH2), 55.4 (OCH3), 30.7 (CH2), 14.4 (CH3); IR tion mixture was warmed slowly to room temperature and stir-
νmax cm−1: 1719 (CvO). MS (EI) m/z 290 (M•+, 100%), 245 (32), ring was continued in the dark overnight. The benzene was
244 (88), 215 (43); HRMS found: 290.1152; C16H18O5•+ requires: evaporated and the residue was partitioned between 1 M HCl
290.1154.
(50 mL) and EtOAc (15 mL). Oxalic acid was added to help
break down the tin complex. The layers were separated and
the aqueous phase was extracted with EtOAc (4 × 20 mL). The
4-(3,5-Dimethoxybenzyl)-3-furoic acid (33)
Aqueous 20% (w/v) sodium hydroxide (4 mL) was added to a combined organic phase was washed with saturated NaHCO3
solution of 32 (95 mg, 0.33 mmol) in MeOH (4 mL) and a (2 × 20 mL), H2O (20 mL) and brine (2 × 20 mL), dried and
white precipitate formed immediately. Upon heating to reflux evaporated to give 36 as a yellow solid (140 mg, 82%). Rf
for 1 h this dissolved to give a colourless solution. After (EtOAc–hexanes 1 : 4) 0.15; IR νmax cm−1: 1703 (CvO); 1H NMR
cooling, the reaction solution was poured into ice-cold 1 M (600 MHz, CDCl3) δ 8.07 (d, J3,1 = 1.2 Hz, 1H, H3), 7.46 (m, 1H,
HCl (40 mL), whereupon a white precipitate formed. The sus- H1), 6.49 (s, 1H, H6), 4.05 (br d, J9,1 = 1.2 Hz, 2H, CH2), 3.96 (s,
pension was extracted with EtOAc (4 × 40 mL) and the organic 6H, 2 × OCH3); 13C NMR (150.9 MHz, CDCl3) δ 179.9 (CvO),
extract was washed with H2O (40 mL) and brine (40 mL), dried 162.2 (ArO), 159.1 (ArO), 144.1 (C1), 142.1 (C8a), 138.5 (C3),
and concentrated to give 33 as a white solid (86 mg, quant.), 124.0 (C3a), 119.8 (C9a), 117.0 (C4a or 8), 113.9 (C4a or 8), 95.1
which crystallised from EtOH as colourless needles, m.p. = (C6), 56.5 (OCH3), 56.3 (OCH3), 24.3 (CH2); MS (EI) m/z 280
1
107–115 °C. Rf (EtOAc–hexanes 1 : 1) 0.45; H NMR (400 MHz, (37Cl M•+, 32%), 278 (35Cl M•+, 100), 249 (57), 213 (24); HRMS
CDCl3) δ 8.08 (d, J2,5 = 1.6 Hz, 1H, H2), 7.08 (dt [app. q], J5,2
=
found: 278.0349; C14H1135ClO4•+ requires: 278.0346.
J5,CH2 = 1.5 Hz, 1H, H5), 6.42 (d, J2′/6′,4′ = 3 Hz, 2H, H2′/H6′),
6.34 (t, J4′,2′/6′ = 3 Hz, 1H, H4′), 3.94 (br s, 2H, CH2), 3.77 (s,
Methyl 4-(3,5-dimethoxybenzoyl)-3-furoate (37)
6H, 2 × OCH3), 1.65 (v br s, OH + H2O); 13C NMR (100 MHz, A 1.3 M solution of BuLi in hexanes (4.45 mL, 5.70 mmol) was
CDCl3) δ 168.5 (CvO), 160.9 (C3′/5′), 150.6 (C2), 142.4 (C5), added to a stirred solution of 1-bromo-3,5-dimethoxybenzene
142.0 (C1′), 125.1 (C3), 117.6 (C4), 107.1 (C2′/C6′), 98.4 (C4′), (1.30 g, 6.00 mmol) in anhydrous THF (25 mL) under argon at
55.4 (OCH3), 30.6 (CH2); IR νmax cm−1: br 3600–2400 (OH), −78 °C. After stirring for 30 min, the solution of aryllithium 25
1687 (CvO); MS (EI) m/z 262 (M•+, 100%), 244 (30), 216 was added dropwise to dimethyl furan-3,4-dicarboxylate (21)
•+
(20), 215 (21); HRMS found: 262.0839; C14H14O5 requires: (1.05 g, 5.68 mmol) in THF (40 mL) at −78°, whereupon the
262.0841; Microanalysis found: C 64.1, H 5.1%; calculated for solution immediately turned orange. The reaction mixture was
C14H14O5: C 64.1, H 5.4%.
allowed to warm slowly to room temperature over 4.5 h then
quenched with saturated NH4Cl (5 mL). The reaction mixture
was extracted with EtOAc (3 × 80 mL) and the extract was
4-(3,5-Dimethoxybenzyl)furan-3-carbonyl chloride (34)
Oxalyl chloride (0.5 mL) was added to 33 (27 mg, 0.10 mmol) washed with brine (50 mL), dried and evaporated to yield a
under argon at 0 °C, whereupon a gas was immediately yellow oil (1.70 g), which was subjected to RSF. Elution with
evolved. The reaction mixture was warmed to room tempera- EtOAc–hexanes (1 : 9) gave 37 as a white solid (368 mg, 21%),
ture over 1 h and stirred in darkness overnight. Excess oxalyl which crystallised from hexanes as white chunky crystals, m.p.
chloride was evaporated under reduced pressure affording 34 = 85–88 °C. Rf (EtOAc–hexanes 1 : 4): 0.2. IR (thin film) νmax
as a brown oil (28 mg, quant.), which was used without purifi- cm–1: 1731 (OCvO); 1666 (CvO). 1H NMR (300 MHz) δ 8.04
cation in the following step. Rf (EtOAc–hexanes 1 : 9) 0.4; IR (d, J = 1.6 Hz, 1H, furyl), 7.72 (d, J = 1.7 Hz, 1H, furyl), 7.00
1
νmax cm−1: 1766 (CvO). H NMR (400 MHz, CDCl3) δ 8.21 (d, (d, J = 2.3 Hz, 2H, H2′/H6′), 6.67 (t, J = 2.3 Hz, 1H, H4′), 3.82
J2,5 = 1.5 Hz, 1H, H2), 7.14 (m, 1H, H5), 6.37 (d, J2′/6′,4′ = 2 Hz, (s, 6H, 2 × OCH3), 3.70 (s, CO2CH3). 13C NMR (75.5 MHz) δ
2H, H2′/H6′), 6.34 (t, J4′,2′/6′ = 2 Hz, 1H, H4′), 3.87 (br s, 2H, 183.3 (CvO), 162.2 (CO2), 160.6 (ArO), 148.3 (α-furyl), 145.6
CH2), 3.77 (s, 6H, 2 × OCH3); 13C NMR (100 MHz, CDCl3) δ (α-furyl), 139.4 (C1′), 125.0 (β-furyl), 118.9 (β-furyl), 107.1 (C2′/
161.0 (CvO), 159.4 (C3′/5′), 154.5 (C2), 143.4 (C5), 140.9 (C1′), C6′), 105.7 (C4′), 55.6 (OCH3), 51.2 (CO2CH3); Microanalysis
125.1 (C3 or 4), 123.5 (C3 or 4), 107.1 (C2′/C6′), 98.6 (C4′), 55.4 found: C 62.0, H 4.6%; calculated for C15H14O6: C 62.1,
(OCH3), 30.4 (CH2); MS (EI) m/z 282 (37Cl M•+, 22%), 280 H 4.9%.
(35Cl M, 66), 245 (100), 244 (66); HRMS found: 280.0507;
4-(3,5-Dimethoxybenzoyl)-3-furoic acid (38)
C14H1335ClO4•+ requires: 280.0502.
Method A. LiOH (130 mg, 3.1 mmol) was added to a stirred
suspension of 49 (180 mg, 0.60 mmol) in 3 : 1 MeOH–H2O
8-Chloro-5,7-dimethoxynaphtho[2,3-c]furan-4(9H)-one (36)
Phosphorus pentachloride (150 mg, 0.72 mmol) was added to (8 mL) at 0 °C and the reaction mixture was stirred at 4 °C, in
a stirred suspension of 33 (160 mg, 0.61 mmol) in anhydrous the dark, for 5 d. The reaction mixture was washed with ether
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(30 mL) and carefully acidified (2 M HCl). The aqueous phase nitrogen overnight. The reaction mixture was diluted with 1 M
was extracted with EtOAc (4 × 50 mL) and the organic extract HCl (10 mL) then extracted with ether (3 × 20 mL). The extract
was evaporated to give 38 as a tan solid (166 mg; quant.), was dried and evaporated to yield a yellow solid (12 mg), which
which crystallised from EtOH as very pale yellow needles, m.p. was purified using preparative TLC. Elution with EtOAc–
= 174–177 °C. Rf (EtOAc–Hex 2 : 3 + 3 drops AcOH) 0.45; IR hexanes–AcOH (50 : 50 : 0.1) gave 42 as a white solid (12 mg,
νmax cm−1: 3500–2800 (OH), 1735 (OCvO), 1686 (CvO); 1H 50%), m.p. = 124–130 °C. Rf (EtOAc–hexanes 1 : 1 + 3 drops
NMR (500 MHz, CDCl3) δ 13.41 (v. br s, 1H, OH), 8.31 (d, J2,5
1.5 Hz, 1H, H2), 8.06 (d, J5,2 = 1.5 Hz, 1H, H5), 6.93 (d, J2′/6′,4′
=
=
AcOH): 0.45. IR (thin film) νmax cm−1: 2750–3850 (OH), 1651
(br 2 × CvO). H NMR (600 MHz, d6-DMSO) major rotamer δ
1
2.5 Hz, 2H, H2′/6′), 6.74 (t, J4′,2′/6′ = 2.5 Hz, 1H, H4′), 3.86 (s, 8.33 (br s, 1H, furyl), 8.00 (s, 1H, furyl), 7.38 (d, J = 7.4 Hz, 2H,
6H, 2 × OCH3); 13C NMR (125.7 MHz; CDCl3) δ 193.9 (CvO), ArH), 7.35–7.30 (m, 3H, ArH), 4.65 (s, 2H, CH2), 2.74 (s, 3H,
161.6 (CO2H), 161.2 (C3′/5′), 154.0 (C2 or 5), 153.2 (C2 or 5), CH3); minor rotamer δ 8.29 (br s, 1H, furyl), 7.93 (s, 1H, furyl),
138.9 (C1′), 122.6 (C3 or 4), 120.0 (C3 or 4), 107.4 (C2′/C6′), 7.26 (app. t, 3H, ArH) 7.21 (d, J = 7.3 Hz, 2H, ArH), 4.38 (s, 2H,
105.9 (C4′), 55.9 (OCH3); MS (EI) m/z 276 (M, 100%), 139 (42), CH2), 2.81 (s, 3H, CH3).
•+
86 (18), 84 (28); HRMS found: 276.0629, C14H12O6 requires:
276.0634; Microanalysis found: C 61.0, H 4.2%; calculated for
MnO2 oxidation of 29
C14H12O6: C 60.9, H 4.4%.
The yield of the analogous reaction from 37 (10 mg, (740 mg, 2.8 mmol) in anhydrous CH2Cl2 (10 mL) under argon
0.035 mmol) was 88%. and the suspension was stirred for 72 h. Filtration of the reac-
MnO2 (1.2 g, 14 mmol) was added to a stirred solution of 29
Method B. A 2.0 M solution of BuLi in hexanes (125 μL, tion mixture followed by evaporation gave an orange oil, which
0.251 mmol) was added to a solution of 1-bromo-3,5-dimethoxy- was subjected to RSF. Elution with EtOAc–hexanes (1 : 9) gave
benzene (49 mg, 0.24 mmol) in anhydrous THF (2 mL) at 43 (323 mg, 42%) identical with the material described below.
−78 °C under argon. After stirring for 30 min, the solution of Further elution with EtOAc–hexanes (1 : 9) gave (Z)-ethyl 4-(3,5-
the aryllithium 25 was added dropwise to a suspension of dimethoxyphenyl)-4-oxobut-2-enoate (44) as a colourless oil
anhydrous CuCN (131 mg, 1.46 mmol) and LiCl (124 mg, (377 mg, 51%). Rf (EtOAc–hexanes 1 : 9) 0.30; IR νmax cm–1:
1
2.93 mmol) in anhydrous THF (3 mL) at −78°, whereupon the 1721 (OCvO), 1672 (CvO). H NMR (500 MHz, CDCl3) δ 7.08
solution turned yellow. The reaction mixture was warmed to (d, J2′/6′,4′ = 2.5 Hz, 2H, H2′/6′), 6.84 (d, J3,2 = 12 Hz, 1H,
−40° for 20 min to ensure complete formation of the organo- vinylic), 6.66 (t, J4′,2′/6′ = 2.5 Hz, 1H, H4′), 6.25 (d, J2,3 = 12 Hz,
cuprate, whereupon the solution turned blue. The solution 1H, vinylic), 4.07 (q, J = 7 Hz, 2H, OCH2), 3.82 (s, 6H, 2 ×
was cooled to −78° and a solution of 41 (35 mg, 0.25 mmol) in OCH3), 1.11 (t, J = 7 Hz, 3H, CH3); 13C NMR (125.8 MHz,
anhydrous THF (1 mL) was added dropwise. The reaction CDCl3) δ 193.9 (CvO), 164.9 (CO2), 161.1 (C3′/5′), 141.1
mixture was allowed to warm to room temperature over 6 h (vinylic), 137.9 (C1′), 126.3 (vinylic), 106.6 (C2′/6′), 106.3 (C4′),
then quenched with 1 M HCl (2 mL), diluted with ether 61.3 (OCH2), 55.7 (OCH3), 13.9 (CH3); MS (EI) m/z 264 (M•+,
(30 mL) and extracted with saturated aqueous NaHCO3 solu- 38%), 191 (100), 137 (23), 122 (30); HRMS found: 264.1009;
tion (3 × 20 mL) whereupon a white precipitate formed. The C14H16O5•+ requires: 264.0998.
precipitate was filtered and the aqueous filtrate was carefully
Ethyl 4-(3,5-dimethoxyphenyl)-4-oxobut-2-ynoate (43)
acidified (1 M HCl, 0 °C) then extracted with EtOAc (4 ×
25 mL). The extract was dried and evaporated to give 38 as a (3-Ethoxy-3-oxoprop-1-ynyl)silver (48)32 (270 mg, 1.3 mmol)
yellow glassy solid (13 mg, 20%), spectroscopically identical was added to a stirred solution of 3,5-dimethoxybenzoyl chlor-
with the material described above.
ide (47)33 (230 mg, 1.2 mmol) in anhydrous toluene (4 mL)
under argon. The reaction mixture was stirred at 90 °C for 72 h
at which point no starting material 47 was detectable by TLC
Furo[3,4-c]furan-1,3-dione (41)
A
solution of 3,4-furandicarboxylic acid (40)19 (279 mg, (EtOAc–hexanes 1 : 9). After cooling, the reaction mixture was
1.80 mmol) in Ac2O (5 mL) under N2 was heated under reflux concentrated and subjected to RSF. Elution with EtOAc–
overnight, during which time the solution turned brown. The hexanes (1 : 19) gave 43 as a bright yellow, light-sensitive solid
volatiles were evaporated and the crude product was subjected (306 mg, 90%), which crystallised from hexanes as yellow
to Kuegelrohr distillation (170–210° at 1 mmHg) to give 41 as needles, m.p. = 61–63 °C. Rf (EtOAc–hexanes 1 : 4) 0.55; IR νmax
white crystals (35 mg, 13%), m.p. = 103–106°. Rf (EtOAc– cm–1: 1719 (OCvO), 1650 (CvO); 1H NMR (400 MHz, CDCl3) δ
hexanes 1 : 1): 0.1. IR (thin film) νmax cm–1: 1860 (antisym. 7.25 (d, J2′/6′,4′ = 2.4 Hz, 2H, H2′/6′), 6.74 (t, J4′,2′/6′ = 2.4 Hz, 1H,
1
CvO), 1798 (sym. CvO). H NMR (300 MHz, CDCl3) δ 8.01 (s, H4′), 4.34 (q, J = 7.2 Hz, 2H, OCH2), 3.85 (s, 6H, 2 × OCH3),
2H, furyl). 13C NMR (75.5 MHz) δ 155.2 (CvO), 141.3 (CH), 1.37 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
121.6. Microanalysis found: C 52.3, H 1.5%; calculated for 176.0 (CvO), 161.2 (CO2), 152.4 (C3′/5′), 137.6 (C1′), 107.9
C6H2O4: C 52.2, H 1.5%.
(C4′), 107.5 (C2′/6′), 80.5 (C2 or 3), 79.9 (C2 or 3), 63.2 (OCH2),
55.9 (OCH3), 14.1 (CH3); MS (EI) m/z 262 (M•+, 94%), 189 (38),
165 (40), 162 (100); HRMS found: 262.0844; C14H14O5
4-(Benzyl(methyl)carbamoyl)-3-furoic acid (42)
•+
A solution of N-methylbenzylamine (2.0 mL, 15 mol) and 41 requires: 262.0841; Microanalysis found: C 63.9, H 5.3%; calcu-
(15 mg, 0.11 mmol) in anhydrous DCM was stirred under lated for C14H14O5 C 64.1, H 5.4%.
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Ethyl 4-(3,5-dimethoxybenzoyl)-3-furoate (49)
CDCl3) δ 8.30 (d, J2,5 = 1.5 Hz, 1H, H2), 7.78 (d, J5,2 = 1.5 Hz,
1H, H5), 6.99 (d, J2′/6′,4′ = 2 Hz, 2H, H2′/6′), 6.70 (t, J4′,2′/6′
=
A solution of hydroquinone (13 mg), 43 (563 mg, 2.15 mmol)
and 4-phenyloxazole 3024 (1.56 g, 10.8 mmol) in anhydrous
toluene (40 mL) under argon was heated at 90 °C in the dark
for 20 h. TLC (EtOAc–hexanes 1 : 9) after this time showed that
the starting material 43 had been consumed. The solvent was
evaporated and the residue was subjected to RSF. Elution with
EtOAc–hexanes (1 : 19) gave excess phenyloxazole 30 followed
by 49 as a colourless solid (554 mg, 85%), which crystallised
from MeOH as white needles, m.p. = 55–56 °C. Rf (EtOAc–
hexanes 1 : 4) 0.35; IR νmax cm−1: 1723 (OCvO), 1665 (CvO);
1H NMR (500 MHz, CDCl3) δ 8.04 (d, J2,5 = 1.5 Hz, 1H, H2),
7.72 (d, J5,2 = 1.5 Hz, 1H, H5), 7.00 (d, J2′/6′,4′ = 2.5 Hz, 2H, H2′/
6′), 6.67 (t, J4′,2′/6′ = 2.5 Hz, 1H, H4′), 4.14 (q, J = 7 Hz, 2H,
OCH2), 3.82 (s, 6H, 2 × OCH3), 1.18 (t, J = 7 Hz, 3H, CH3); 13C
NMR (125.7 MHz, CDCl3) δ 188.9 (CvO), 162.1 (CO2), 160.9
(C3′/5′), 148.4 (α-furyl), 145.9 (α-furyl), 139.9 (C1′), 125.3
(β-furyl), 119.6 (β-furyl), 107.4 (C2′/C6′), 105.9 (C4′), 61.1
(OCH2), 55.8 (OCH3), 14.0 (CH3); MS (EI) m/z 304 (M•+, 100%),
2.5 Hz, 1H, H4′), 3.83 (s, 6H, 2 × CH3O); 13C NMR (125.7 MHz,
CDCl3) δ 187.1 (CvO), 161.1 (C3′/5′), 157.8 (ClCO), 153.5
(α-furyl), 147.4 (α-furyl), 139.1 (C1′), 124.8 (β-furyl), 124.0
(β-furyl), 107.6 (C2′/C6′) 106.2 (C4′), 55.8 (CH3O); MS (EI) m/z
296 (37Cl M•+, 12%), 294 (35Cl M•+, 33), 259 (100), 229 (23);
HRMS found: 294.0295; C14H1135ClO5•+ requires: 294.0289.
5-Hydroxy-7-methoxynaphtho[2,3-c]furan-4,9-dione,
(monosporascone) (4)
Freshly sublimed AlCl3 (68 mg, 0.51 mmol) was added to a
stirred solution of 51 (30 mg, 0.10 mmol) in DCE (1 mL) under
argon at 0 °C. The reaction mixture was allowed to warm to
room temperature and stirring was continued in the dark for
8 d, after which time the reaction mixture was diluted with ice-
cold 2 M HCl (40 mL) and saturated with oxalic acid. The
aqueous phase was extracted with EtOAc (3 × 60 mL) and the
extract was evaporated to give a rust-coloured solid, which was
subjected to RSF. Elution with (MeOH–DCM 1 : 99) gave mono-
sporascone 1 (18 mg, 75%) as a bright yellow solid, which crys-
tallised from hexanes–EtOAc as yellow-green crystals, m.p. =
226–240 °C [lit.16 205–215 °C (decomp.)]. Rf (MeOH–DCM
1 : 99) 0.65; IR νmax cm−1: 3700–2900 (OH), 1670 (CvO), 1628
(CvO). 1H NMR (500 MHz, CDCl3) δ 12.89 (s, 1H, OH), 8.20
(d, J3,1 = 1.5 Hz, 1H, α-furyl), 8.19 (d, J1,3 = 1.0 Hz, 1H, α-furyl),
7.37 (d, J8,6 = 2.5 Hz, 1H, H8), 6.69 (d, J6,8 = 2.5 Hz, 1H, H6),
3.93 (s, 3H, CH3O); 13C NMR (125.7 MHz, CDCl3) δ 184.0 (C4),
178.7 (C9), 166.5 (C7), 166.3 (C5), 146.4 (α-furyl), 145.9
(α-furyl), 137.4 (C8a), 123.0 (C3a or C9a), 122.9 (C3a or C9a)
112.3 (C4a), 108.3 (C8), 106.8 (C6), 56.2 (CH3O); MS (EI) m/z
244 (M•+, 59%), 88 (100), 83 (30), 81 (27); HRMS found:
•+
260 (33), 259 (16), 139 (47); HRMS found: 304.0951; C16H16O6
requires: 304.0947; Microanalysis found: C 63.1, H 5.3%; calcu-
lated for C16H16O6 C 63.2, H 5.3%.
5,7-Dimethoxynaphtho[2,3-c]furan-4,9-dione (monosporascone
methyl ether) (14)
PCl5 (23 mg, 0.11 mmol) was added to a stirred solution of 38
(30 mg, 0.11 mmol) in anhydrous benzene (1 mL) under argon
and the reaction mixture was heated under reflux. After 1 h,
the reaction mixture was cooled to 0 °C and a solution of
SnCl4 (65 μL, 0.55 mmol) in anhydrous benzene (1 mL) was
added, whereupon the solution turned yellow. The reaction
mixture was stirred at room temperature for 24 h then
quenched with ice-cold 2 M HCl (30 mL) and saturated with
oxalic acid. The aqueous phase was extracted with EtOAc (4 ×
20 mL) and the extract was dried and evaporated to yield an
orange solid (10 mg). Purification by preparative TLC (EtOAc–
hexanes 1 : 4 with 10 drops AcOH) gave 14 as an orange solid
(1 mg, 4%), m.p. = 111–113°. Rf (1 : 4 EtOAc–hexanes + 3 drops
AcOH): 0.2. IR (thin film) νmax cm–1: 1733 (CvO), 1667(CvO).
1H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 1.3 Hz, 1H, furyl),
8.11 (d, J = 1.3 Hz, 1H, furyl), 7.47 (d, J = 2.4 Hz, 1H, ArH), 6.79
(d, J 2.4 Hz, 1H, ArH), 3.99, (s, 3H, OCH3), 3.98, 3H, s, OCH3.
13C NMR (150.9 MHz, CDCl3) δ 177.9 (CO), 174.5 (CO), 145.5
(α-furyl), 145.2 (α-furyl), 139.7, 136.5, 124.2, 104.6 (ArH), 103.8
(ArH), 56.5 (OCH3), 55.9 (OCH3). Three quaternary carbons
were not observed due to the paucity of material available.
•+
244.0370; C13H8O5 requires: 244.0372. The spectroscopic
data matched those reported.15
5-Hydroxy-7-methoxy-1,3-dihydronaphtho[2,3-c]furan-4,9-dione
(dihydromonosporascone) (5)
To a stirred solution of 1 (6 mg, 0.025 mmol) in anhydrous
AcOH (2 mL) under argon was added zinc powder (140 mg)
and the reaction mixture was heated to 100 °C for 2 h. The
yellow solution was cooled and diluted with water (20 mL)
then extracted with EtOAc (4 × 20 mL) and evaporated to give
an orange oil. Preparative TLC (MeOH–DCM 1 : 99) gave three
coloured bands, the middle one being 2, which was recovered
as a yellow solid (2 mg, 33%). 1H NMR (500 MHz, CDCl3) δ
12.06 (s, 1H, OH), 7.19 (d, J8,6 = 2.5 Hz, 1H, H8), 6.64 (d, J6,8
=
2.5 Hz, 1H, H6), 5.13 (d, J1,3 = 2.5 Hz, 4H, 2 × H1, 2 × H3), 3.91
(s, 3H, CH3O). The 1H NMR spectrum matched the reported
data.15
4-(3,5-Dimethoxybenzoyl)furan-3-carbonyl chloride (50)
SOCl2 (500 μL) was added to 38 (36 mg, 0.13 mmol) at 0 °C
under argon. The acid dissolved slowly (over 5 h) producing a
pale yellow solution. After stirring overnight in the dark, excess
thionyl chloride was evaporated under reduced pressure
Acknowledgements
affording 50 as a brown oil, which was used without purifi- We acknowledge the facilities, and scientific and technical
cation in the following step. Rf (EtOAc–hexanes 1 : 4) 0.25; IR assistance, of the Australian Microscopy and Microanalysis
νmax cm−1: 1773 (ClCvO), 1666 (CvO). 1H NMR (500 MHz, Research Facility at the Centre for Microscopy, Characteris-
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Organic & Biomolecular Chemistry
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