Efficient formal synthesis of (±)-hyphodermin B

Article abstract of DOI:10.1021/jo052485l

An efficient formal synthesis of hyphodermin B 1, a metabolite of Hyphoderma radula, has been completed in 15% overall yield. The tricyclic carbon skeleton 3 was rapidly assembled from a novel vinyl enone via a Diels-Alder reaction, followed by dehydrogen

Full text of DOI:10.1021/jo052485l

Efficient Formal Synthesis of (()-Hyphodermin B
Luke C. Henderson, Wendy A. Loughlin,*,† Ian D. Jenkins, Peter C. Healy,† and
Marc R. Campitelli
Natural Product DiscoVery, Griffith UniVersity, Brisbane, QLD, 4111, Australia, and School of Science
and Eskitis Institute, Griffith UniVersity, Brisbane, QLD, 4111, Australia
w.loughlin@griffith.edu.au
ReceiVed December 1, 2005
An efficient formal synthesis of hyphodermin B 1, a metabolite of Hyphoderma radula, has been completed
in 15% overall yield. The tricyclic carbon skeleton 3 was rapidly assembled from a novel vinyl enone
via a Diels-Alder reaction, followed by dehydrogenation and anhydride formation. Selective reduction
of anhydride 3 with LiAlH(t-BuO)3 gave hyphodermin B 1 in 99% yield. The structure of hyphodermin
B 1 was confirmed by X-ray crystallographic analysis. The anhydride 3, bearing a γ-carbonyl group,
displayed unexpected reactivity with the anhydride carbonyl closest to the γ-ketone being the most
electrophilic site. This was confirmed by HF/6-31G* calculations. In the presence of base, 3 underwent
a rearrangement to the novel lactone 16.
Introduction
(()-Hyphodermin B 1 is a novel naphtho[1,2-c]furan-3,9-
dione isolated from a culture of the basidiomycete Hyphoderma
radula (WP 2184), obtained from the trunk of a wild cherry
tree in Wuppertal (Germany), as the major metabolite in
conjunction with other metabolites, hyphodermins A and C-H.1
Biological studies identified these metabolites as being potential
drug leads for the treatment and prophylaxis of asthma and
chronic bronchitis as well as of heart and CNS illnesses.1
Hyphodermin B 1 was first isolated in 1995 and reported as a
racemic mixture at C1. The structure of 1 was determined by
1H NMR spectroscopy,1 but a synthesis of 1 has not been
reported. Literature syntheses of related compounds containing
an aromatic lactol structure (3-hydroxyphthalide) are limited.
For example, the simple antibacterial corollosporine2 (Figure
1) has been made, whereas syntheses of more complex structures
such as betonicoside,3 betonicolide,3 betolide4 (Figure 1), and
jusmicranthin5 remain unreported. The biological activity and
novel skeleton incorporating the 3-hydroxyphthalide and adja-
FIGURE 1. Some 3-hydroxyphthalide natural products.
cent ketone make hyphodermin B 1 a challenging and important
synthetic target.
Considering the synthesis of 1, a literature survey revealed
that incorporation of the lactol unit in simple aromatic com-
pounds was not straightforward. Reduction of phthalic anhy-
drides was often complicated by overreduction6,7 and generation
of regioisomers.7 Alternative routes required the lactol to be
generated via unstable trimethylsiloxy isobenzofurans8 or as the
byproduct from oxidation of aromatic dialdehydes.9 Retrosyn-
(3) Miyase, T.; Yamamoto, R.; Ueno, A. Chem. Pharm. Bull. 1996, 44,
1610.
(4) (a) Bankova, V.; Koeva-Todorovska, J.; Stambolijska, T.; Ignatova-
Groceva, M.-D.; Todorova, D.; Popov, S. Z. Naturforsch., C: Biosci. 1999,
54, 876. (b) Tkachev, V. V.; Nikonov, G. K.; Atovmyan, L. O.; Kobzar,
A. Ya.; Zinchenko, T. V. Khim. Prir. Soedin. 1987, 811.
(5) Rajasekhar, D.; Subbaraju, G. V. Fitoterapia 2000, 71, 598.
* To whom correspondence should be addressed. Phone: + (07) 3735 7567.
Fax: + (07) 3735 7656.
† School of Science and Eskitis Institute.
(1) Henkel, T.; Mueller, H.; Schmidt, D.; Wollweber, H. New natural
Substances of hyphodermins and chemical derivatives. Ger. Offen. DE
19611366, 1997; SciFinder Scholar AN, 1997: 651311.
(2) Ohzeki, T.; Mori, K. Biosci. Biotechnol. Biochem. 2001, 65, 172.
10.1021/jo052485l CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/11/2006
2384
J. Org. Chem. 2006, 71, 2384-2388

Efficient Formal Synthesis of (()-Hyphodermin B
SCHEME 1. Synthetic Approach to Hyphodermin B
SCHEME 2. Synthesis of Alkoxyenones 6-9a
a Reagents and conditions: (a) 10% HCl, MeOH or EtOH; (b) p-
toluenesulfonic acid, MeOH; (c) TiCl4, MeOH or EtOH, Et3N, room
temperature.
SCHEME 3. Synthesis of Anhydride 3a
TABLE 1. Formation of Alkoxyenones 6-9 from Diketone 5
product ratio yield
entry
reaction conditions
alcohol products
6 and 7
6/7 or 8/9
%
1
2
3
10% HCl, reflux, 16 h EtOH
1:2
1:2
1:2.5
47
39
49
10% HCl, reflux, 16 h MeOH 8 and 9
p-toluenesulfonic acid, MeOH 8 and 9
reflux, 90 min
4
5
(a) TiCl4, 15 min;
(b) Et3N, 45 min
(a) TiCl4, 15 min;
(b) Et3N, 45 min
MeOH 8 and 9
1:7
1:2
90
37
EtOH 6 and 7
thetic analysis of hyphodermin B 1 (Scheme 1) suggested that
elaboration of anhydride 3 to acid aldehyde 2, followed by ring
closure of 2 at equilibrium, could give the lactol group of
hyphodermin B 1. The ring system of anhydride 3 could be
formed through a Diels-Alder reaction on enone 4 and
anhydride formation from a diacid precursor. Herein, we report
the first total synthesis of hyphodermin B 1 from diketone 5
via anhydride 3.
a Reagents and conditions: (a) CeCl3, BrMgCHdCH2, THF, room
temperature, 16 h, 93%; (b) dimethylacetylene dicarboxylate, 1% hydro-
quinone, toluene, reflux, 60 h; 10 6%, 11 17%; (c) dimethylacetylene
dicarboxylate, 1% hydroquinone, toluene, reflux, 60 h then Pd/C, acetic
acid, reflux, 24 h, 11 from 4 in 57%; (d) 10% NaOH, reflux, 3.5 h; 2 M
HCl, 91%; (e) acetic anhydride, 50 °C, 16 h, 88%.
Results and Discussion
Initially, we planned to form vinylcyclohexenone 410 via a
1,4-addition of vinylmagnesium bromide to ethoxyenone 6.
Ethoxyenones 6 and 711 and methoxyenones 8 and 9 were
obtained by treatment of diketone 5 with ethanolic HCl or
methanolic HCl or methanol and p-toluenesulfonic acid, re-
spectively (entries 1-3, Table 1; Scheme 2). A trial reaction
of purified methoxyenone 8 with vinylmagnesium bromide led
to the recovery of unreacted 8. It was considered that 1,2-
addition of the Grignard to the isomeric methoxyenone 9,
catalyzed by cerium(III) chloride,12 might provide an alternative
route to 4. A marked improvement in the yield of methoxyenone
9 from diketone 5 was observed when the diketone 5 was treated
with titanium(IV) tetrachloride in methanol13 (entry 4, Table 1;
Scheme 2). Thus, the synthesis of anhydride 3 was continued
using methoxyenone 9, with application of aspects of the
methodology used for the synthesis of angucyclinones.14
Addition of cerium(III) chloride to methoxyenone 9 for 1 h
followed by addition of vinylmagnesium bromide and stirring
at room temperature for 12 h gave vinylcyclohexenone 4 in high
yield (93%) and purity (>95%). The crude product was used
immediately in the next step as it decomposes on storage or
attempted chromatographic purification. Diels-Alder reaction
of vinylcyclohexenone 4 with dimethylactetylene dicarboxylate
in refluxing toluene for 60 h, under an atmosphere of nitrogen
or air, gave a mixture of hexahydronaphthalene dimethylester
10 and tetrahydronaphthalene dimethylester 11 in a ratio of 40:
60 (nitrogen; 54%) or 20:80 (air; 42%) for 10/11, respectively
(Scheme 3). The difference in the ratio of 10/11 obtained is
suggestive of autoxidation of 10 occurring in situ. Various
oxidation reagents have been used to dehydrogenate polycyclic
hydroaromatic compounds.15 Isolated hexahydronaphthalene
dimethylester 10 was unstable upon isolation and storage but
could be directly converted to tetrahydronaphthalene dimethyl-
(6) (a) Donati, C.; Prager, R. H.; Weber, B. Aust. J. Chem. 1989, 42,
787. (b) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C.-C.; Chauret,
N.; Desmarais, S.; Dube´, D.; Falgueyret, J.-P.; Fortin, R.; Guay, J.; Hamel,
P.; Jones, T. R.; Le´pine, C.; Li, C.; McAuliffe, M.; McFarlane, C. S.; Nicoll-
Griffith, D. A.; Riendeau, D.; Yergey, J. A.; Girard, Y. J. Med. Chem.
1996, 39, 3951.
(7) (a) Sugimoto, A.; Tanaka, H.; Eguchi, Y.; Ito, S.; Takashima, Y.;
Ishikawa, M. J. Med. Chem. 1984, 27, 1300. (b) Coucy, C.; Favreau, D.;
Kayser, M. M. J. Org. Chem. 1987, 52, 129.
(12) (a) Majetich, G.; Zhang, Y.; Feltman, T. L.; Duncan, S., Jr.
Tetrahedron Lett. 1993, 34, 445. (b) Greeves, N.; Lyford, L. Tetrahedron
Lett. 1992, 33, 4759. (c) Dimitrov, V.; Bratovanov, S.; Simova, S.; Kostova,
K. Tetrahedron Lett. 1994, 35, 6713.
(8) Troll, T.; Schmid, K. Tetrahedron Lett. 1984, 25, 2981.
(9) Moriconi, E. J.; O’Connor, W. F.; Wallenberger, F. T. J. Am. Chem.
Soc. 1959, 81, 6466.
(10) Akai, S.; Tanimoto, K.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43,
1407.
(11) Foote, K. M.; Hayes, C. R. J.; John, M. P.; Pattenden, G. Org.
Biomol. Chem. 2003, 1, 3917.
(13) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron 2001, 57, 217.
(14) Rozek, T.; Janowski, W.; Hevko, J. M.; Tiekink, E. R. T.; Dua, S.;
Stone, D. J. M.; Bowie, J. H. Aust. J. Chem. 1998, 51, 5153.
(15) Fu, P. P.; Harvey, R. G. Chem. ReV. 1978, 78, 317.
J. Org. Chem, Vol. 71, No. 6, 2006 2385

Henderson et al.
ester 11 (70%) by heating at reflux overnight with Pd on
charcoal in toluene (DDQ gave no reaction). However, we found
a more efficient process. A crude mixture of 10 and 11 was
heated at reflux in acetic acid with Pd/C which resulted in
conversion of 10 to 11. Using the Diels-Alder reaction and
then Pd/C oxidation as a two-step process, we easily converted
diene 4 to tetrahydronaphthalene dimethylester 11 in 57%
overall yield (Scheme 3).
Treatment of isolated hexahydronaphthalene dimethyl ester
10 with sodium hydroxide at reflux gave diacid 12 (89%).
However, the problems with isolation of 10 prevented scale-
up. Instead, treatment of tetrahydronaphthalene dimethylester
11 with sodium hydroxide at reflux for 3 h, followed by
acidification, gave 12 (91%) (Scheme 3). This was converted
to the anhydride 3 (88%) by treatment with acetic anhydride16
at 50 °C overnight. Use of refluxing acetic anhydride with or
without an acid catalyst (H2SO4) led to concurrent formation
of the enol acetate 13 (typically 10%). In summary, anhydride
3 was made in five steps from diketone 5 and in 15%
unoptimized overall yield. Elaboration of anhydride 3 to
hyphodermin B 1 was examined next.
FIGURE 2. Representation of energy-minimized structure of 3
(Spartan 04, V1.0.1, HF/6-31G*). For clarity, the LUMO map has been
adjusted to make only the most electron-deficient region of 3 visible
(shown in blue then green).
Formation of lactone 16 also occurred in 46% yield when
anhydride 3 was treated with DMAP and triethylamine in
refluxing toluene in the absence of tert-butyl alcohol. This
suggested that nucleophilic attack on anhydride 3 by DMAP
followed by attack of the enol on the resultant acylpyridinium
intermediate gives ring closure to lactone 16. As the tert-butyl
ester 14 was unable to be obtained, we turned our attention to
formation of a benzyl ester, which could be selectively cleaved
by catalytic hydrogenation. Treatment of anhydride 3 with
sodium benzyloxide in THF gave benzyl ester 19 (24%). The
regiochemistry of addition at C1 was confirmed through
gCOSY, gHSQC, and gHMBC spectroscopy. The carbonyl
peaks of the carboxylic acid/benzyl ester groups at C1 and C2
were coincident at 400 MHz but resolvable at 600 MHz (δ
169.0, 169.3 ppm) allowing the regiochemical assignment to
be made. Because of the formation of lactone 16 and the
unexpected regioselectivity of the ring opening of anhydride 3
by benzyl alcohol, modeling studies on anhydride 3 were carried
out at the HF/6-31G* level using Spartan 04.18
The energy-minimized structure of anhydride 3 is shown in
Figure 2. The LUMO was mapped onto the electron density
surface and then adjusted to make only the most electron-
deficient region visible. This resulted in identification of regions
of 3 most susceptible to nucleophilic attack. Notably, electron
deficiency is heavily centralized on C1 of the anhydride ring
of 3. The modeling results support the experimental observations
seen with the reaction of anhydride 3 with methanol and benzyl
alcohol. This suggested that the direct and regioselective
reduction of anhydride 3 to the lactol represented by hypho-
dermin B 1 (Scheme 1) was feasible.
It was envisaged that the anhydride 3 could be ring opened
regioselectively with tert-butyl alcohol to give the acid 14 (it
was assumed that C1 of anhydride 3 would be sterically hindered
to attack). Subsequent reduction of the carboxylic acid of 14 to
a primary alcohol followed by PCC oxidation to aldehyde 15
and TFA cleavage of tert-butyl ester 15 should give acid
aldehyde 2. In the event, anhydride 3 was treated with tert-
butyl alcohol, DMAP, triethylamine, and N-hydroxysuccinimide
and heated at reflux in toluene according to a literature
procedure.17 Surprisingly, lactone 16 was obtained along with
recovery of anhydride 3 (45:55, anhydride/lactone, 48%).
However, purification and full characterization of lactone 16
was complicated by partial hydrolysis of lactone 16 to diacid
12, which occurred rapidly upon standing. The structure of 16
was further confirmed by reduction of 16 with sodium boro-
hydride in THF and methanol to give the stable ether derivative
17. The connectivity of ether 17 was unequivocally assigned
using gCOSY, gHSQC, and gHMBC spectroscopy. In addition,
methyl ester 18 was isolated and assumed to have arisen from
nucleophilic attack of methanol on lactone 16.
Initial attempts at reduction of the C1 carbonyl group of
anhydride 3 with DIBALH at 0 °C gave 50% conversion to
lactone 16 or a complex mixture. Formation of lactone 16 may
be facilitated by a diisobutylaluminum enolate19 intermediate,
such as 20, acting as a nucleophile to open and activate the
anhydride for internal displacement. By changing the reducing
(16) Brown, R. F. C.; Coulston, K. J.; Eastwood, F. W.; Saminathan, S.
Aust. J. Chem. 1987, 40, 107.
(17) ) (a) Liu, F.; Zha, H.-Y.; Yao, Z.-J. J. Org. Chem. 2003, 68, 6679.
(b) Guzzo, P. R.; Miller, M. J. J. Org Chem. 1994, 59, 4862. (c) Lelais, G.;
Campo, M. A.; Kopp, S.; Seebach, D. HelV. Chim. Acta 2004, 87, 1545.
(18) ) Spartan ’04; Wavefunction Inc.: Irvine, CA.
(19) 9) For example: Groth, U.; Koehler, T.; Taapken, T. Tetrahedron
1991, 47, 7583.
2386 J. Org. Chem., Vol. 71, No. 6, 2006

Efficient Formal Synthesis of (()-Hyphodermin B
Experimental Section
4,4-Dimethyl-3-vinylcyclohex-2-en-1-one 4. A solution of 9
(6.28 g, 41 mmol) in anhydrous THF (20 mL) was added to cerium-
(III) chloride (1.1 g, 4.5 mmol). The suspension was stirred at room
temperature for 1 h. Vinylmagnesium bromide was added (52 mL).
The resulting solution was stirred at room temperature overnight.
Ammonium chloride (saturated, 15 mL) then hydrochloric acid (2
M, 30 mL) were added, and the combined aqueous phase was
extracted with ether (3 × 40 mL). The combined organic phases
were washed with hydrochloric acid (1 × 40 mL), sodium
bicarbonate (3 × 25 mL), and brine (3 × 30 mL) and dried (MgSO4,
anhydrous), and the solvent was removed in vacuo. Crude 410 (5.74
mg, 93%) was obtained as an unstable dark yellow oil. Analysis
by 1H NMR spectroscopy showed 4 in >95% purity. 1H NMR (400
MHz, CDCl3): δ ) 1.16 (s, 6 H, 2 × CH3), 1.84 (t, 2 H, J ) 6.8
Hz, 2 × H5), 2.46 (t, 2 H, J ) 6.4 Hz, 2 × H6), 5.34 (dd, 1 H,
J ) 1.2, 11 Hz, CHdCH2), 5.67 (dd, 1 H, J ) 1.2, 17.2 Hz,
CHdCH2), 6.04 (s, 1 H, H2), 6.46 (ddd, 1 H, J ) 0.8, 11.2, 17.7
Hz, CHdCH2). 13C NMR (100 MHz, CDCl3): δ ) 26.8 (2 × CH3),
34.5 (C5), 34.6 (C4), 37.6 (C6), 120.2 (CHdCH2), 122.6 (C2),
134.2 (CHdCH2), 166.7 (C3), 199.9 (CdO). HREIMS calcd for
C10H14O m/z 150.1045, found m/z 150.1048.
FIGURE 3. Representation of the dimeric H-bonding structure of 1
(H2‚‚‚O4i ) 1.84, O2‚‚‚O4i ) 2.728(6) Å, and O2-H2‚‚‚O4i ) 165°
[symmetry code (i) - x, 1 - y, 2 - z]).
agent to LiAlH(t-BuO)3, we anticipated that acid/base effects
should be diminished and reduction at the most electron-
deficient carbonyl (C1) of anhydride 3 promoted. Anhydride 3
was reacted with LiAlH(t-BuO)3 at 0 °C for 4 h, and hypho-
dermin B 1 was isolated as a racemic mixture in 99% yield.
This result, together with the formation of 18 and 19 and the
molecular modeling studies above, suggests that electronic
factors are responsible for the regioselective reactions of the
1
anhydride 3. The H NMR spectrum of synthetic (()-hypho-
dermin B 1 in d4-methanol was consistent with the reported 1H
NMR data for (()-hyphodermin B1 1 isolated from Hyphoderma
radula.
Dimethyl 5,5-Dimethyl-8-oxo-3,4,5,6,7,8-hexahydronaphtha-
lene-1,2-dicarboxylate 10 from 4 with Reflux in Air. Dimethy-
lacetylene dicarboxylate (116 mg, 0.813 mmol, 0.14 mL) and 4
(111 mg, 0.739 mmol) in toluene (5 mL) were heated at reflux for
60 h under an air atmosphere. The solvent was removed in vacuo.
The crude mixture was obtained as an oil (254 mg) and was purified
by silica gel chromatography (ethyl acetate/hexane 1:1). Fraction
The synthetic sample of hyphodermin B 1 crystallizes from
chloroform as pale yellow square plates suitable for the single-
crystal X-ray structure determination. A representative view of
the molecular structure of 1 is shown in Figure 3. In this
structure, the benzofuranone ring system is essentially planar.
The carbonyl oxygen atom O4 lies 0.24 Å out of the plane with
the pseudo torsion angle Oa-C9‚‚‚C9b-C1 ) -12.3(5)°.
Difference Fourier maps showed elongated residual electron
density about the C7 atom above and below the plane of the
cyclohexanone ring. This was modeled as two disordered C
atoms with 50% occupancy. Residual electron density in the
vicinity of the C1 proton suggested the presence of minor
enantiomeric disorder in the crystal lattice. This was modelled
with occupancy factors of 0.9 for the major component and
0.1 for the minor component. In the crystal lattice, pairs of
molecules associate across a center of symmetry through
1
1 gave 11 (37 mg, 17%) as identified by H NMR spectroscopy.
Fraction 2 gave 10 (9 mg, 6%) as an unstable yellow powder after
drying. Mp 120-122 °C. 1H NMR (400 MHz, CDCl3): δ ) 1.23
(s, 6 H), 1.90 (t, J ) 3.2 Hz, 2 H), 2.4-2.5 (m, 4 H), 2.52 (t, J )
3.4 Hz, 2 H), 3.76 (s, 3 H), 3.86 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ ) 22.8, 24.8, 26.3, 34.1, 36.2, 36.3, 52.2, 52.4, 126.6,
128.1, 135.2, 166.6, 169.2, 170.7, 194.2. HREIMS calcd for
C16H20O5 m/z 292.1310, found m/z 292.1314.
Dimethyl 5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-
1,2-dicarboxylate 11 from 4. Dimethylacetylene dicarboxylate (3.1
g, 21.8 mmol, 2.7 mL) and hydroquinone (1%) were added to a
stirred solution of crude 4 (2.86 g, 19.1 mmol) in anhydrous toluene
(30 mL). The resulting solution was heated at reflux in air for 60
h. The solvent was removed in vacuo to give a yellow resin. The
crude product was dissolved in acetic acid (30 mL) and heated at
reflux in the presence of Pd/C (10%, 600 mg) for 24 h in air. The
suspension was filtered through Celite, and the filtrate was
evaporated to dryness under reduced pressure. Analysis by 1H NMR
spectroscopy of the crude mixture obtained indicated the presence
of 11, acetic acid, and water (6.51 g). The crude mixture was
purified by silica gel chromatography (ethyl acetate/hexane 50:50).
Fraction 1 gave 11 as an orange viscous oil (3.14 g, 57%). 1H NMR
(200 MHz, CDCl3): δ ) 1.41 (s, 6 H), 2.03 (t, J ) 6.6 Hz, 2 H),
2.76 (t, J ) 7.4 Hz, 2 H), 3.90 (s, 3 H), 4.02 (s, 3 H), 7.57 (d, J )
8.4 Hz, 1 H), 8.17 (d, J ) 8.4 Hz, 2 H). 13C NMR (50 MHz,
CDCl3): δ ) 29.9, 35.0, 35.4, 36.2, 52.8, 52.9, 126.6, 127.4, 129.2,
134.9, 136.1, 157.5, 165.1, 168.8, 196.6. Anal. Calcd for C16H18O5‚
H2O: C, 62.33%; H, 6.54%. Found: C, 62.55%; H, 6.52%.
classical R2 (14)i O-H‚‚‚O intermolecular hydrogen-bonding
2
interactions20 between the hydroxy proton and the carbonyl
oxygen, with H2a‚‚‚O4i ) 1.75, O2a‚‚‚O4i ) 2.724(5) Å,
and O2a-H2a-O4i ) 165° (symmetry code (i) - x, 1 - y ,
2 - z]).
Conclusions
Total synthesis of (()-hyphodermin B 1 was achieved from
diketone 5 in six steps and 15% overall yield. Notably, the
synthesis was developed without the need for complex protec-
tion-deprotection strategies and exploited the unexpected
regioselective reduction of anhydride 3. The solid-state structure
of 1 is reported for the first time. Computer modeling studies
of 3 and X-ray crystallographic data for 1 provide supporting
evidence for the unexpected reactivity of C1 of anhydride 3 to
oxygen nucleophiles. With synthetic quantities of hyphodermin
B 1 now in hand, further investigations into the biological
activity of hyphodermin B 1 and its simple derivatives will be
carried out.
5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-1,2-dicar-
boxylic Acid 12. Compound 11 (527 mg, 1.82 mmol) was dissolved
in sodium hydroxide (10%, 10 mL), heated at reflux in air for 3.5
h, and worked up as above. Compound 12 was obtained as an
orange foam (435 mg, 91%) in >95% purity after drying, as
1
determined by analysis by H NMR spectroscopy. Mp 266-267
°C. 1H NMR (200 MHz, d6-DMSO): δ ) 1.36 (s, 6 H), 1.97 (t, J
) 6.8 Hz, 2 H), 2.70 (d, J ) 7.2 Hz, 2 H), 3.34 (s, 2 H), 7.69 (d,
J ) 8.8 Hz, 1 H), 8.03 (d, J ) 8 Hz, 1 H). 13C NMR (100 MHz,
d6-DMSO): δ ) 29.2, 34.5, 35.0, 35.5, 126.9, 127.6, 128.4, 134.1,
(20) ) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1555.
J. Org. Chem, Vol. 71, No. 6, 2006 2387

Henderson et al.
136.2, 156.3, 166.4, 169.2, 196.4. HREIMS calcd for C14H14O5 m/z
262.0841, found m/z 262.0843.
Hz, 1 H), 7.99 (d, J ) 8 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ ) 29.2, 30.2, 35.2, 35.6, 36.7, 97.4, 127.2, 129.7, 130.4, 132.4,
148.3, 160.0, 167.0, 199.7. Anal. Calcd for C14H14O4: C, 68.28%;
H, 5.73%. Found: C, 68.36%; H, 6.10%.
6,6-Dimethyl-7,8-dihydronaphtho[1,2-c]furan-1,3,9(6H)-tri-
one 3. Compound 12 (1.68 g, 6.41 mmol) was dissolved in acetic
anhydride (12 mL), and the solution was heated to 50 °C overnight
under a nitrogen atmosphere. The acetic anhydride was removed
in vacuo to give a black resin. The crude resin was azeotroped
with toluene (20 mL) to give 3 (1.37 g, 88%) as a gray powder.
Mp 229-231 °C. 1H NMR (200 MHz, CDCl3): δ ) 1.46 (s, 6 H),
2.12 (t, J ) 7.0 Hz, 2 H), 2.90 (t, J ) 7.2 Hz, 2 H), 7.96 (d, J )
8.0 Hz, 1 H), 8.10 (d, J ) 8.2 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): δ ) 29.7, 35.7, 35.8, 36.5, 128.4, 131.8, 132.6, 134.1,
136.9, 159.3, 161.3, 162.4, 194.8. HREIMS calcd for C14H12O4 m/z
244.0736, found m/z 244.0735.
Computer Calculations. All calculations were performed using
Spartan 04 (Windows Edition) V1.0.118 on a dual-core Pentium
III Xeon (2 × 1 GHz) running Windows XP Professional SP2.
Equilibrium geometries of 3 were calculated at the HF/6-31G* level
following a preoptimization using the AM1 semiempirical method.
Default optimization parameters were employed. The final geometry
was characterized as an energy minimum on the potential energy
surface by the absence of any negative (imaginary) vibrational
frequencies at the stationary point. The electron density surface is
drawn at an IsoVal of 0.002 electrons/au3 with the LUMO property
map set to a range of 0.020-0.033 eV.
Hydroxy-6,6-dimethyl-7,8-dihydronaphtho[1,2-c]furan-3,9-
(1H,6H)-dione (Hyphodermin B) 1. Compound 3 (50 mg, 0.21
mmol) was added to a solution of lithium tri-tert-butoxyalumino-
hydride (53 mg, 0.21 mmol) in THF (15 mL) at 0 °C. The solution
was stirred at 0 °C for 4 h under a nitrogen atmosphere. Ammonium
chloride (saturated, 5 mL) and hydrochloric acid (2 M, 10 mL)
were added, and the aqueous phase was extracted with DCM (3 ×
30 mL). The combined organic layers were washed with brine (2
× 40 mL) and dried (MgSO4), and solvent was removed in vacuo
to give a brown foam. The crude foam was purified by silica gel
flash chromatography (ethyl acetate/heptane; 1: 1). Compound 1
was obtained as a white powder (51 mg, 99%). Mp dec 200 °C. 1H
NMR (200 MHz, CDCl3): δ ) 1.46 (s, 3 H), 1.47 (s, 3 H), 2.11
(t, J ) 7 Hz, 2 H), 2.84 (t, J ) 7.2 Hz, 2 H), 6.95 (s, 1 H), 7.74
Acknowledgment. Financial support for this work was
provided by (1) Griffith University, (2) Natural Product
Discovery, Griffith University, (3) Eskitis Institute, Griffith
University, and (4) the award of an APAWS to L. C. Henderson.
Supporting Information Available: (1) Additional experimen-
1
tal procedures, (2) MS and FTIR data for 1, 3, 4, 10-12, (3) H
NMR spectra for 1, 3, 4, 6, 10, 12, 13, 17-19, (4) Cartesian
coordinates and computed total energy for 3, (5) crystal data, data
collection, structure solution, and refinement for 1 and ORTEP plot
of conformer 2 for 1, (6) picture of the dimeric H-bonding structure
of 1, and (7) CIF for 1. This material is available free of charge
via the Internet at http:/pubs.acs.org.
1
(d, J ) 8.2 Hz, 1 H), 8.03 (d, J ) 7.8 Hz, 1 H). H NMR (200
MHz, CD3OD): δ ) 1.47 (s, 3 H), 1.49 (s, 3 H), 2.11 (t, J ) 5.4
Hz, 2 H), 2.78 (t, J ) 6.2 Hz, 2 H), 7.06 (s, 1 H), 7.87 (d, J ) 8.2
JO052485L
2388 J. Org. Chem., Vol. 71, No. 6, 2006