Synthesis of triprenylated toluquinone and toluhydroquinone metabolites from a marine-derived Penicillium fungus

Article abstract of DOI:10.1016/j.tetlet.2006.09.117

Two triprenylated toluquinone and toluhydroquinone marine fungal metabolites, 5-methyl-2-[(2′E,6′E)-3′,7′,11′-trimethyl-2′,6′,10′-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione and 5-methyl-2-[(2′E,6′E)-3,7,11-trimethyl-2′,6′,10′-dodecatrienyl]-1,4-benzenediol, were synthesized in four and five steps, respectively, from 2-methyl-1,4-benzoquinone. The synthesis extends the applicability of the oxidative ether cleavage of hydroquinone dimethyl ethers with argentic oxide under acidic conditions to include the oxidative demethylation of polyprenylated-1,4-dimethoxy-toluhydroquinones with a quantitative survival of the oxidation- and acid-sensitive polyprenyl side chain.

Full text of DOI:10.1016/j.tetlet.2006.09.117

Tetrahedron Letters 47 (2006) 8243–8246
Synthesis of triprenylated toluquinone and toluhydroquinone
metabolites from a marine-derived Penicillium fungus
Brent A. Scheepers, Rosalyn Klein and Michael T. Davies-Coleman*
Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa
Received 1 August 2006; revised 7 September 2006; accepted 21 September 2006
Abstract—Two triprenylated toluquinone and toluhydroquinone marine fungal metabolites, 5-methyl-2-[(20E,60E)-30,70,110-tri-
methyl-20,60,100-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione and 5-methyl-2-[(20E,60E)-3,7,11-trimethyl-20,60,100-dodecatrienyl]-
1,4-benzenediol, were synthesized in four and five steps, respectively, from 2-methyl-1,4-benzoquinone. The synthesis extends the
applicability of the oxidative ether cleavage of hydroquinone dimethyl ethers with argentic oxide under acidic conditions to include
the oxidative demethylation of polyprenylated-1,4-dimethoxy-toluhydroquinones with a quantitative survival of the oxidation- and
acid-sensitive polyprenyl side chain.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Triprenylated toluquinone and toluhydroquinone sec-
ondary metabolites have been isolated from both marine
and terrestrial fungi. A marine derived Penicillium spe-
cies afforded 5-methyl-2-[(20E,60E)-30,70,110-trimethyl-
Bohlmann et al. briefly reported the isolation of 1 via
distillation following the MnO2 oxidation of the product
mixture obtained from the reaction of farnesol with 1,4-
dihydroxytoluene, in the presence of a BF3-etherate
Lewis acid catalyst.5 No discussion was presented of
either the regioselectivity, if any, of this reaction or, in
the absence of this discussion a quantification of the
yields of the plethora of different regioisomers and
polyprenylation products, which could reasonably be
expected from this Friedel–Crafts type alkylation reac-
tion involving such a highly activated aromatic precur-
sor. We therefore opted for a different approach as
our primary goal was to find a regiospecific route to 1
and 2, which we could readily exploit for the synthesis
of other prenylated quinones and hydroquinones.
Several strategies are available for the regioselective
synthesis of ortho-prenylated phenols including Claisen
rearrangements, directed ortho-metallation (DoM),
metal mediated coupling, and MHE.7 The latter approach
attracted us given our previous successful use of MHE
methodology to synthesize the marine natural product
tsitsikammafuran 7.8 The success of the MHE approach
initially requires the availability of a suitably halo-
genated, aryl precursor.7 Accordingly, the regiospecific
reductive bromination of 2-methyl-1,4-benzoquinone 8,
originally reported by Miller and Stewart,9 proceeded
smoothly in our hands to give 2-bromo-5-methyl-1,4-
benzenediol 9. The appropriate protection of the pheno-
lic functionalities in 9 and subsequent coupling of the
organolithium reagent derived from protected 9 to a
20,60,100-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione
1
and
5-methyl-2-[(20E,60E)-3,7,11-trimethyl-20,60,100-
dodecatrienyl]-1,4-benzenediol 2,1,2 while grifolin 3 and
neogrifilin 4, isomeric with 2, were obtained from the
inedible mushroom Albatrellus caeruleoporus.3 Com-
pound 1 is not confined to the marine environment
and has also been isolated from Phellinus pini, a terres-
trial fungus pathogenic to conifer trees,4 and from three
species of the terrestrial plant genus Seseli.5 Oxygena-
tion within the triprenyl side chain is a common struc-
tural feature in naturally occurring prenylated
quinones and hydroquinones, for example, A. caeuu-
leoporus is also the source of grifolinone 5,3 while the
South African marine nudibranch Leminda millecra
has yielded 6 and several other metabolites related to 1
and 2.6 The diverse biological activities associated with
this cohort of compounds, including radical scaveng-
ing,1 cytotoxicity,2 and potential anti-inflammatory
properties,3 prompted us to explore the use of metal hal-
ogen exchange (MHE) methodology for the syntheses of
1 and 2.
Keywords: Penicillium; Marine fungus; Triprenyl; Toluhydroquinone;
Toluquinone.
*
Corresponding author. Tel.: +27 46 603 8294; fax: +27 46 622
5109; e-mail: m.davies-coleman@ru.ac.za
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.117

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B. A. Scheepers et al. / Tetrahedron Letters 47 (2006) 8243–8246
14'
R1
15'
13'
O
O
1'
1
2
12'
R4
R2
7
5
1
R3
2
3
4
R1 = R3 =OH, R2 = H, R4 = Me
R1 = R2 = OH, R3 = H, R4 = Me
R1 = Me, R2 = R4 = OH, R3 =H
OH
O
OH
O
OH
OH
6
5
O
HO
O
OH
OH
10
7
prenyl electrophile, for example, farnesyl bromide fol-
lowed by deprotection appeared to be a feasible regio-
specific route to 2 (Scheme 1).
acid 10 also via an MHE strategy.11 Odejinmi and
Wiemer’s benzyl protection was particularly attractive
because the olefins of the farnesyl side chain were im-
mune to the mild deprotection conditions used (heating
with sodium metal). Regrettably, our attempts to couple
the organolithium reagent derived from the benzylated
precursor 11 to prenyl bromides, using the same MHE
protocol reported by Odejinmi and Wiemer for the
preparation of 10, were unsuccessful.
Our choice of a convenient phenol protection/deprotec-
tion strategy was guided by the need to ensure that first,
the protecting group was unaffected by the initial
strongly basic environment necessary for MHE, and
that second, the reaction conditions required for depro-
tection were compatible with the unsaturated triprenyl-
ated side chain. Thus esters, which can be depro-
tonated by n-BuLi, and silyl ethers, which may undergo
a retro-Brook rearrangement,10,11 were rejected in favor
of aryloxy ether protection. Recently, Odejinmi and
Wiemer drew attention to the suitability of benzyl pro-
tection in their synthesis of the E,E-isomer of piperoic
Following this initial setback we turned to the possibility
of protecting 9 as dimethyl ether 12 prior to the MHE
step. Although we recognized at the outset that the
prenyl side chain in 2 would possibly not survive the
harsh Lewis acid-mediated conditions commonly used
for the efficient O-demethylation of phenyl methyl
O
OMe
OMe
OH
Br
Br
d
c
a
OMe
O
OMe
OH
8
14
9
12
e
f, c
e
b
OBn
OMe
1
Br
f
OMe
OBn
2
13
11
Scheme 1. Synthesis of triprenyl toluquinone 1 and triprenyl toluhydroquinone 2 from 2-methyl-1,4-benzoquinone 8. Reagents and conditions:
(a) Me3SiBr, Et4NBF4, MeCN, RT (61%); (b) PhCH2Br, K2CO3, NaI, Ac2O, reflux (80%); (c) NaOH, Me2SO4, reflux (70%); (d) TMEDA, n-BuLi,
farnesyl bromide, Et2O 0 ꢁC (27%); (e) AgO, dioxane, HNO3, rt (98%); (f) Na2S2O4, 1:3 DCM/Et2O, rt (98%).

B. A. Scheepers et al. / Tetrahedron Letters 47 (2006) 8243–8246
8245
ethers, we were encouraged by several reports in which
References and notes
milder conditions had been used successfully to accom-
plish this transformation in selected examples, for exam-
ple, deprotection with L-Selectride,12 trimethylsilyl
iodide,13 and an intriguing ‘phase vanishing’ reaction
using perfluorohexane as a phase screen and boron
tribromide as the dealkylating agent.14 In addition, an
alternative approach to direct demethylation is the oxi-
dative demethylation of 1,4-dimethoxyhydroquinones
to yield 1,4-benzoquinones.15,16 After preliminary
deprotection studies on the simple toluhydroquinone di-
methyl ether 13, we opted for the simple oxidative cleav-
age approach of Snyder and Rapoport,15 in which 1,4-
hydroquinone dimethyl ethers are efficiently cleaved
with argentic oxide17 to afford 1,4-benzoquinones. De-
spite the strongly acidic conditions required for this
transformation, we surmised that given the short length
of time (<2 min) that a 1,4-dioxane solution of the
prenylated toluhydroquinone would be stirred with a
6 N nitric acid solution of argentic oxide, it would be
unlikely that the prenyl side chain would be adversely
affected. We accordingly methylated 9 with dimethyl
sulfate in the usual manner to give 12 and were subse-
quently able to successfully couple the organolithium
reagent derived from this compound with farnesyl
bromide to afford 14 in a moderate yield.18 It is impor-
tant to note that the coupling could only be achieved in
dry diethyl ether solutions at 0 ꢁC in the presence of
TMEDA (1.5 equiv) and all attempts to carry out this
reaction in dry THF at various temperatures and differ-
ent concentrations of either CuBrÆDMS or TMEDA
were unsuccessful. Interestingly, Odejinmi and Wiemer
also found THF to be an unsuitable solvent for MHE
and subsequent prenylation during their synthesis of
10.11
1. Li, X.; Choi, H. D.; Kang, J. S.; Lee, C.; Son, B. W. J.
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2. Son, B. W.; Kim, J. C.; Choi, H. D.; Kang, J. S. Arch.
Pharm. Res. 2002, 25, 77–79.
3. Quang, D. N.; Hashimoto, T.; Arakawa, Y.; Kohchi, C.;
Nishizawa, T.; Soma, G.-I.; Asakawa, Y. Bioorg. Med.
Chem. 2006, 14, 164–168.
4. Ayer, W. H.; Muir, D. J.; Chakravarty, P. Phytochemistry
1996, 42, 1321–1324.
5. Bohlmann, F.; Zdero, C.; Suwita, A. Chem. Ber. 1975,
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6. McPhail, K. L.; Davies-Coleman, M. T.; Starmer, J. J.
Nat. Prod. 2001, 64, 1183–1190.
7. Hoarau, C.; Pettus, T. R. R. Synlett 2003, 127–137.
8. McPhail, K. L.; Rivett, D. E. A.; Lack, D. E.; Davies-
Coleman, M. T. Tetrahedron 2000, 56, 9391–9396.
9. Miller, L. L.; Stewart, R. F. J. Org. Chem. 1978, 43, 3078–
3079.
10. Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104,
2667–2722.
11. Odejinmi, S. I.; Wiemer, D. F. Tetrahedron Lett. 2005, 46,
3871–3874.
12. Coop, A.; Janetka, J. W.; Lewis, J. W.; Rice, K. C. J. Org.
Chem. 1998, 63, 4392–4396.
13. Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Mahotra, R.
J. Org. Chem. 1979, 44, 1247–1251.
14. Ryu, I.; Matsubara, H.; Yasuda, S.; Nakamura, H.;
Curran, D. P. J. Am. Chem. Soc. 2002, 124, 12946–12947.
15. Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94,
227–231.
16. Bernini, R.; Mincione, E.; Barontini, M.; Fabrizi, G.;
Pasqualetti, M.; Tempesta, S. Tetrahedron 2006, 62, 7733–
7737.
17. Hammer, R. N.; Kleinberg, J. Inorg. Synth. 1953, 4, 12–13.
18. Preparation of 14. A solution of 12 (309 mg, 1.34 mmol),
TMEDA (0.30 mL, 2 mmol) and n-BuLi (2 mmol) in dry
Et2O (2 mL) was stirred (15 min) at 0 ꢁC before the
addition of farnesyl bromide (0.36 mL, 1.34 mmol). The
solution was allowed to stir overnight and the reaction was
finally quenched with satd NH4Cl (5 mL) and extracted
with ether (2 · 5 mL). The Et2O fractions were combined,
washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. Normal phase HPLC (10 hexane:
1 EtOAc) purification of the product mixture afforded 14
(0.129 g) as a yellow oil. UV (MeOH) kmax 290 (e 2487),
230 (e 3305) nm; 13C NMR (100 MHz, CDCl3) 151.6
(C-4), 151.0 (C-1), 136.1 (C-30), 135.0 (C-70), 131.2 (C-110),
128.0 (C-2), 124.4 (C-60 and C-100), 124.2 (C-5), 122.7 (C-
20), 114.1 (C-6), 112.4 (C-3), 56.3 (OMe), 56.1 (OMe), 39.8
(C-40), 39.7 (C-80), 28.2 (C-10), 26.8 (C-50 and C-90), 25.7
(C-120), 17.7 (C-130), 16.1 (C-150 and C-140), 16.0 (C-7);
1H NMR (400 MHz, CDCl3) 6.67 (s, 1H, H-6), 6.66 (s,
1H, H-3), 5.31 (t, J 7.23, 1H, H-20), 5.13 (t, J 6.51, 1H, H-
60) 5.09 (t, J 6.51, 1H, H-100), 3.77 (s, 3H, OMe), 3.76 (s,
3H, OMe), 3.30 (d, J 7.21, 1H, H-10), 2.20 (s, 3H, 3H-7),
2.05 (m, 8H, 2H-40, 2H-80, 2H-50 and 2H-90), 1.71 (s, 3H,
3H-150), 1.67 (s, 3H, 3H-120), 1.60 (s, 3H, 3H-130), 1.59 (s,
3H, 3H-140); HRFABMS [M+] 356.2714 (calcd for
C24H36O2 356.2715).
As hoped, the oxidative demethylation of 14 proceeded
quantitatively to afford 1.19 The absence of any cycliza-
tion, oxidation or acid-induced degradation of the tri-
prenyl side chain during the argentic oxide mediated
oxidative demethylation of 14 suggests that Snyder
and Rapoport’s15 methyl ether protection/oxidative
deprotection strategy might find wide applicability to
the synthesis of other prenylated 1,4-toluquinones. The
reduction of 1 with sodium dithionite20 gave 2 in a quan-
titative yield and the spectroscopic data of both com-
pounds were consistent with literature values reported
for these two compounds.1,2,4,5
Acknowledgments
Financial assistance from the South African National
Research Foundation, Department of Environmental
Affairs and Tourism, Rhodes University, and the Mel-
lon Foundation (R.K.) is gratefully acknowledged.
19. Oxidative demethylation of 14. A solution of 14 (190 mg,
0.53 mmol), freshly prepared AgO17 (71 mg, 0.58 mmol)
and dry 1,4-dioxane (2 mL) was briefly sonicated to obtain
a uniform distribution of the oxidant. 6 N HNO3 (0.2 mL)
was added with stirring and the reaction mixture allowed
to proceed until most of the AgO had been consumed
(<2 min). The reaction was quenched by the addition of
CHCl3–H2O (10 mL, 4:1). The CHCl3 fraction was
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
09.117.

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B. A. Scheepers et al. / Tetrahedron Letters 47 (2006) 8243–8246
separated, washed with H2O (3 · 4 mL) to remove excess
with a freshly prepared solution of sodium dithionite
(330 mg, 1.89 mmol) in H2O (4 mL). The organic layer
was separated, washed with brine (2 · 5 mL), dried over
anhydrous MgSO4, filtered and concentrated under
acid, dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo to give 1 as a bright yellow oil (170 mg).
UV, 1H and 13C NMR data was consistent with published
values.5–8 HRFABMS [M+H]+ 327.2323 (calcd for
C22H31O2 327.2324).
1
reduced pressure to give 2 as a brown oil (80 mg). UV, H
and 13C NMR data was consistent with published
values.5–8 HRFABMS [M+] 328.2403 (calcd for
C22H32O2 328.2402).
20. Reduction of 1. A solution of 1 (87 mg, 0.27 mmol) in a
mixture (1:3) of DCM–Et2O (4 mL) was shaken (5 min)