Bio-inspired dimerisation of prenylated quinones directed towards the synthesis of the meroterpenoid natural products, the scabellones

Article abstract of DOI:10.1016/j.tetlet.2015.02.024

Stirring 2-geranyl-6-methoxy-1,4-hydroquinone in pyridine/O₂ or 2-geranyl-6-methoxy-1,4-benzoquinone in pyridine/N₂ affords the dimeric meroterpenoid natural products, scabellones A-C in modest to low yields and also identifies 2-methoxy-6-(4-methylpent-3-en-1-yl)-1,4-naphthoquinone (scabellone E) as a new natural product. The corresponding reaction of the des-methoxy analogue, 2-geranyl-1,4-benzoquinone in degassed pyridine for three days afforded the natural product cordiachromene A (15% yield) and 6-(4-methylpent-3-en-1-yl)-1,4-naphthoquinone (12%), the latter being a likely biosynthetic precursor to the marine meroterpenoid alkaloids, conicaquinones A and B.

Full text of DOI:10.1016/j.tetlet.2015.02.024

Tetrahedron Letters 56 (2015) 1486–1488
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bio-inspired dimerisation of prenylated quinones directed towards
the synthesis of the meroterpenoid natural products, the scabellones
⇑
Susanna T. S. Chan , Michael A. Pullar, Iman M. Khalil, Emmanuelle Allouche, David Barker, Brent R. Copp
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1142, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Stirring 2-geranyl-6-methoxy-1,4-hydroquinone in pyridine/O2 or 2-geranyl-6-methoxy-1,4-benzoqui-
none in pyridine/N2 affords the dimeric meroterpenoid natural products, scabellones A–C in modest to
low yields and also identifies 2-methoxy-6-(4-methylpent-3-en-1-yl)-1,4-naphthoquinone (scabellone
E) as a new natural product. The corresponding reaction of the des-methoxy analogue, 2-geranyl-1,4-
benzoquinone in degassed pyridine for three days afforded the natural product cordiachromene A (15%
yield) and 6-(4-methylpent-3-en-1-yl)-1,4-naphthoquinone (12%), the latter being a likely biosynthetic
precursor to the marine meroterpenoid alkaloids, conicaquinones A and B.
Received 21 October 2014
Revised 22 January 2015
Accepted 8 February 2015
Available online 13 February 2015
Keywords:
Meroterpenoid
Dimerisation
Bio-inspired
Ó 2015 Elsevier Ltd. All rights reserved.
Marine natural product
Scabellone
Ascidians belonging to the genus Aplidium (Order Enterogona,
Family Polyclinidae) are known to produce a variety of bioactive
marine natural products.1 We recently described the isolation of
a series of meroterpenoid natural products including scabellones
A (1) and B (2), 2-geranyl-6-methoxy-1,4-hydroquinone-4-sulfate
(3) and 8-methoxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-
benzopyran-6-ol (4) (Fig. 1) from a New Zealand collection of
Aplidium scabellum.2 Scabellone B was identified as a moderately
active antimalarial agent, making it of interest for structure-
activity relationship studies. The pseudodimeric structures of the
scabellones suggested that their biogenesis proceeds via dimerisa-
tion of hydroquinone 5 and/or quinone 6. In continuation of our
studies on the biomimetic synthesis of natural products,3,4 we
herein report on our investigations of bio-inspired coupling reac-
tions of 5 and 6 that afforded scabellones A–C, and which identified
the structurally-related 2-methoxy-6-(4-methylpent-3-en-1-yl)-
1,4-naphthoquinone (7, scabellone E) as a new natural product.
The combination of copper(I) chloride, pyridine and oxygen has
been reported to mimic metal-centred oxidase enzymes as
catalysts for the oxidation and coupling of phenolic compounds.5
Reaction of hydroquinone 5 with O2–CuCl–pyridine at room tem-
perature gave quinone 6 (26%) and 2-methoxy-6-(4-methylpent-
O
O
O
O
MeO
MeO
O
OH
O
OMe
OMe
OH
1
2
OH
OMe
MeO
O
HO
OR
4
3 R = SO3
5
R = H
Figure 1. Structures of the natural products, scabellones A (1) and B (2), quinol
sulfate 3 and chromenol 4, and related hydroquinone 5.
3-en-1-yl)-1,4-naphthoquinone (7)6 (1%), while the reaction
undertaken at 0 °C (ice bath) afforded 6 (24%), 7 (1%) and the
dimeric products, scabellone B (2) (3%) and C (1%) (Scheme 1).
The formation of naphthoquinone 7 under these reaction condi-
tions, albeit in very low yields, was surprising. Previous efforts to
⇑
Corresponding author. Tel.: +64 9 373 7599; fax: +64 64 373 7422.
E-mail address: b.copp@auckland.ac.nz (B.R. Copp).
Current address: Molecular Targets Laboratory, Center for Cancer Research,
National Cancer Institute, Building 562, Frederick, MD 21702, USA.
http://dx.doi.org/10.1016/j.tetlet.2015.02.024
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. T. S. Chan et al. / Tetrahedron Letters 56 (2015) 1486–1488
1487
O
OMe
MeO
MeO
O
O
Δ
1
3
HO
O
HO
(i)
6
7
O
O
OH
OH
2
5
+
Δ
O
8
OMe
1'
3
5
8
9
10
O
Δ saturated
Scheme 1. Reagents and conditions: (i) CuCl, pyridine, O2, 0 °C, 30 min, 2 (3%), 6
(24%), 7 (1%).
Figure 2. Structures of chromenol 8 and chroman 9 dimers and tectol 10.
R
construct such functionalised naphthoquinones typically utilise a
Diels–Alder reaction between benzoquinone and
O
a
-cumene,7
O
O
R
(i)
though an earlier publication by Burnett and Thomson reported
that BF3 diethyl etherate effected the cyclisation of 2-methyl-5-
(3-methylbut-2-enyl)-l,4-benzoquinone to give chimaphilin.8 The
transformation of 5 into 7 can be considered biomimetic as the bio-
synthesis of 2-(4-methylpent-3-en-1-yl)anthraquinone (MPAQ)
has been shown to proceed via 2-geranyl-1,4-naphthoquinone9
and there are numerous reports in the literature of the co-isolation
of prenylated benzoquinones and the corresponding ring-closed
naphthoquinones.10 Indeed, with an authentic sample of naphtho-
quinone 7 in hand, re-examination of the extract fractions of Apli-
dium scabellum derived from our previous efforts to isolate
naturally occurring scabellones A–D led to identification of the
presence of the compound. Thus we have assigned the trivial name
scabellone E to 7.
+
R
O
OH
O
17
14 R = H
R = H
11 R = H
15
18 R = prenyl
12
R = prenyl
R = prenyl
19
16 R = geranyl
R = geranyl
13 R = geranyl
Scheme 3. Reagents and conditions: (i) degassed pyridine, N2, rt, 72 h, 14 (32%), 17
(2%); 15 (52%), 18 (7%); 16 (44%), 19 (1%).
14 (32%)/15 (52%)/16 (44%)13 and naphthoquinones 17 (2%)/18
(7%)/19 (1%)14 (Scheme 3).
In the specific case of the reaction of 2-geranylbenzoquinone
12, in addition to cordiachromene A (15) and 6-(4-methylpent-3-
en-1-yl)-1,4-naphthoquinone (18), 2-geranyl-1,4-hydroquinone
(9%) was identified in the product mixture. This observation sug-
gested that quinone 12 was also an oxidant in the reaction, acting
to oxidise a naphthoquinone precursor. Repeating each of the reac-
tions of 11–13 with the addition of one equivalent of 1,4-benzoqui-
none as a sacrificial co-oxidant afforded slightly increased yields of
naphthoquinones 17–19 (3%, 12% and 9%, respectively). Intrigu-
ingly, in each of these reactions, production of the corresponding
chromenol 14–16 was suppressed. Trialing the addition of two
equivalents of 1,4-benzoquinone to the reaction of 12 gave no fur-
ther increase in the yield of naphthoquinone 18, but did lead to the
production of benzo[c]chromene-7,10-dione 2015 (Fig. 3) in 7%
yield. Naphthoquinone 18 represents the terpenoid core of conic-
aquinones A and B, natural products previously reported from
the Mediterranean ascidian Aplidium conicum.16
Further experiments established pyridine as the only necessary
component for the formation of dimeric products. Thus stirring
hydroquinone 5 in pyridine under O2 at room temperature for
30 min yielded the dimeric products scabellone A (1) and B (2),
as well as chromenol 4, quinone 6, and naphthoquinone
7
(Scheme 2).
The corresponding reaction of quinone 6 in pyridine, degassed
and under nitrogen and stirred overnight, afforded scabellone A
(1) (9%) and chromenol 4 (10%), but only trace amounts of the
dimeric products, scabellone B (2), scabellone C, and dichromenol
811 (Fig. 2).
Extending this latter reaction to three days using degassed pyr-
idine afforded a complex mixture of products, from which chro-
menol 4 (5%) and naphthoquinone 7 (8%) were purified. The
generality of the transformation of quinone 6 into naphthoquinone
7 in pyridine was investigated using structurally simpler benzoqui-
none analogues 11, 12 and 13.4,12 In each case, stirring in degassed
pyridine at room temperature for three days afforded complex
mixtures, from which were isolated the corresponding chromenols
We have recently reported that the reaction of 12 with Et3N in
CH2Cl2 followed by overnight oxidation over silica gel afforded
OMe
1'
O
2
HO
5
O
O
O
4
OH
O
MeO
MeO
MeO
OH
O
O
MeO
(i)
+
+
O
OH
OMe
OMe
6
O
O
5
OH
MeO
1
2
O
7
Scheme 2. Reagents and conditions: (i) pyridine, O2, rt, 30 min, 1 (11%), 2 (3%), 4 (trace), 6 (1.5%), 7 (1.5%).

1488
S. T. S. Chan et al. / Tetrahedron Letters 56 (2015) 1486–1488
5. Kametani, T.; Ihara, M.; Takemura, M.; Satoh, Y.; Terasawa, H.; Ohta, Y.;
O
O
Fukumoto, K.; Takahashi, K. J. Am. Chem. Soc. 1977, 99, 3805–3808.
6. Data for 7: Rf (CH2Cl2) 0.57; IR vmax (ATR) 1683, 1652, 1609, 1243 cmꢀ1
,
1H NMR
O
(CDCl3, 400 MHz) d 8.04 (1H, d, J = 8.0 Hz, H-5), 7.90 (1H, d, J = 1.6 Hz, H-6),
7.51 (1H, dd, J = 8.0, 1.6 Hz, H-8), 6.14 (1H, s, H-2), 5.12 (1H, m, H-30), 3.90 (3H,
s, 3-OCH3), 2.77 (2H, t, J = 7.5 Hz, H2-10), 2.35 (2H, td, J = 7.5 Hz, H2-20), 1.67
(3H, s, H3-60), 1.53 (3H, s, H3-50); 13C NMR (CDCl3, 100 MHz) d 185.3 (C-1),
180.0 (C-4), 160.6 (C-3), 150.0 (C-7), 133.6 (C-8), 133.2 (C-40), 132.0 (C-8a),
129.1 (C-4a), 126.9 (C-5), 126.1 (C-6), 122.6 (C-30), 109.7 (C-2), 56.4 (3-OCH3),
36.3 (C-10), 29.3 (C-20), 25.6 (C-60), 17.7 (C-50); (+)-HRESIMS m/z 271.1322
[M+H]+ (calcd for C17H19O3, 271.1329).
HO
20
Figure 3. Structure of benzo[c]chromene-7,10-dione 20.
7. Gordaliza, M.; Miguel del Corral, J. M.; Castro, M. A.; Mahiques, M. M.; Garcia-
Gravalos, M. D.; San Feliciano, A. Bioorg. Med. Chem. Lett. 1996, 6, 1859–1864.
8. Burnett, A. R.; Thomson, R. H. J. Chem. Soc. C 1968, 857–860.
dimers that could be elaborated into thiaplidiaquinones A and B,
which are cytotoxic thiazinoquinones also isolated from Aplidium
conicum.4 Using similar reaction conditions with quinone 6 affor-
ded only complex mixtures from which no individual products
could be purified.
9. Furumoto, T.; Hoshikuma, A. Phytochemistry 2011, 72, 871–874.
10. Sunassee, S. N.; Davies-Coleman, M. T. Nat. Prod. Rep. 2012, 29, 513–535.
11. Data for 8: Rf (MeOH/CH2Cl2, 1:9) 0.63; IR (ATR) mmax 3446, 2929, 1583, 1443,
1198 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 6.55 (2H, s, H-7), 5.89 (2H, d,
J = 9.9 Hz, H-4), 5.58 (2H, d, J = 9.9 Hz, H-3), 5.08 (2H, t, J = 7.1 Hz, H-30), 4.55
(2H, s, OH), 3.88 (6H, s, OCH3-10), 2.12 (4H, m, H2-20), 1.76 (2H, m, H2-10a), 1.67
(2H, obscured, H2-10b), 1.66 (6H, s, H3-50), 1.57 (6H, s, H3-60), 1.43 (6H, s, H3-9);
13C NMR (CDCl3, 125 MHz) d 150.0 (C-8), 148.2 (C-6), 136.5 (C-8a), 132.0 (C-3,
40), 124.2 (C-30), 122.0 (C-4a), 120.4 (C-4), 105.8 (C-5), 100.3 (C-7), 77.9 (C-2),
56.3 (C-10), 40.4 (C-10), 26.0 (C-9), 25.8 (C-50), 22.8 (C-20), 17.7 (C-60); (+)-
HRESIMS [M+H]+ 547.3065 (calcd for C34H43O6, 547.3054).
It has been previously reported that phenyliodine(III) bis(tri-
fluoroacetate) (PIFA) can be activated with BF3.Et2O to promote
oxidative carbon–carbon bond formation.17 Using hydroquinone
5 as the starting material, reaction at 0 °C in dry acetonitrile
yielded only benzoquinone 6 and no oxidative coupling products.
However, when the temperature was decreased to ꢀ40 °C and
the solvent changed to dry CH2Cl2, chroman dimer 918 was formed
(62%) (Fig. 2). Repeating the reaction using chromenol 4 as the
starting material afforded dichromenol 8 (89%). While we and
others have found that reaction of the dichromenol tectol (10) with
chloranil effects ring closure to yield the 9,10-dihydropyrano-
benzo[c,f]chromene-1,4-dione natural product tecomaquinone I,3
efforts directed towards effecting a similar ring closure of 8 or 9
to yield scabellones C/D were unsuccessful.
In conclusion, we have achieved a bio-inspired synthesis of the
meroterpenoids scabellone A–C, finding that the reaction of 2-ger-
anyl-6-methoxy-1,4-hydroquinone in pyridine under O2 or 2-gera-
nyl-6-methoxy-1,4-benzoquinone in pyridine under N2 affords the
dimeric natural products in modest to low yields. The study also
identified 2-methoxy-6-(4-methylpent-3-en-1-yl)-1,4-naphtho-
quinone as a new natural product (scabellone E).
12. (a) Mehta, G.; Pan, S. C. Org. Lett. 2004, 6, 811–813; (b) Mehta, G.; Pan, S. C.
Tetrahedron Lett. 2005, 46, 5219–5223.
13. Spectroscopic data observed for 14–16 agreed with those previously reported
in the literature: (a) Pelter, A.; Hussain, A.; Smith, G.; Ward, R. S. Tetrahedron
1997, 53, 3879–3916; (b) Kim, I. K.; Park, S. K.; Erickson, K. L. Magn. Reson.
Chem. 1993, 31, 788–789.
14. Data for 17: Rf (hexane/CH2Cl2, 1:2) 0.61; IR (ATR)
mmax 2925, 1662, 1598, 1305,
822 cmꢀ1 1H NMR (CDCl3, 400 MHz) d 7.98 (1H, d, J = 8.0 Hz, H-8), 7.89 (1H, d,
;
J = 2.0 Hz, H-5), 7.55 (1H, dd, J = 8.0, 2.0 Hz, H-7), 6.94 (2H, s, H-2/H-3), 2.51
(3H, s, H3-10); 13C NMR (CDCl3, 100 MHz) d 185.4 (C-1/C-4), 145.1 (C-6), 138.8
(C-2), 138.5 (C-3), 134.6 (C-7), 131.8 (C-4a), 130.1 (C-8a), 126.8 (C-5), 126.6 (C-
8), 21.9 (C-10). Data for 18: Rf (hexane/CH2Cl2, 1:2) 0.72; IR (ATR) mmax 3682,
2923, 2866, 1664, 1601, 1304, 1055, 1033, 1012, 833, 754 cmꢀ1 1H NMR
;
(CDCl3, 400 MHz) d 7.99 (1H, d, J = 8.0 Hz, H-8), 7.90 (1H, d, J = 2.0 Hz, H-5),
7.56 (1H, dd, J = 8.0, 2.0 Hz, H-7), 6.95 (2H, s, H-2/H-3), 5.13 (1H, m, H-30), 2.78
(2H, t, J = 8.0 Hz, H2-10), 2.35 (2H, dt, J = 8.0, 7.5 Hz, H2-20), 1.67 (3H, s, H3-50),
1.53 (3H, s, H3-60); 13C NMR (CDCl3, 100 MHz) d 185.4 (C-4), 185.0 (C-1), 149.5
(C-6), 138.8 (C-2), 138.5 (C-3), 134.2 (C-7), 133.2 (C-40), 131.8 (C-4a), 129.9 (C-
8a), 126.6 (C-5), 126.2 (C-8), 122.6 (C-30), 36.3 (C-10), 29.3 (C-20), 25.7 (C-50),
17.7 (C-60); (+)-HRESIMS [M+H]+ m/z 241.1225 (calcd for C16H16O2, 241.1223).
Data for 19: Rf (hexane/CH2Cl2, 1:2) 0.68; IR (ATR)
mmax 2922, 2856, 1666, 1601,
1303, 833 cmꢀ1 1H NMR (CDCl3, 400 MHz) d 7.99 (1H, d, J = 7.9 Hz, H-8), 7.90
;
(1H, d, J = 1.6 Hz, H-5), 7.56 (1H, dd, J = 7.9, 1.6 Hz, H-7), 6.94 (2H, s, H-2/H-3),
5.14 (1H, m, H-30), 5.06 (1H, m, H-70), 2.79 (2H, t, J = 7.5 Hz, H2-10), 2.36 (2H, q,
J = 7.5 Hz, H2-20), 2.03 (2H, m, H2-60), 1.98 (2H, m, H2-50), 1.67 (3H, d, J = 1.0 Hz,
H3-90), 1.59 (3H, s, H3-100), 1.53 (3H, s, H3-110); 13C NMR (CDCl3, 100 MHz) d
185.4 (C-4), 185.0 (C-1), 149.5 (C-6), 138.8 (C-3), 138.5 (C-2), 136.8 (C-40),
134.2 (C-7), 131.8 (C-4a), 131.5 (C-80), 129.9 (C-8a), 126.6 (C-5), 126.3 (C-8),
124.2 (C-70), 122.4 (C-30), 39.7 (C-50), 36.3 (C-10), 29.2 (C-20), 26.6 (C-60), 25.7
(C-90), 17.7 (C-100), 16.0 (C-110); (+)-HRESIMS [M+Na]+ m/z 331.1673 (calcd for
Acknowledgment
We acknowledge the University of Auckland for funding.
Supplementary data
C
21H24NaO2, 331.1669).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.02.
024. These data include MOL files and InChiKeys of the most
important compounds described in this article.
15. Carbone, A.; Lucas, C. L.; Moody, C. J. J. Org. Chem. 2012, 77, 9179–9189.
16. Aiello, A.; Fattorusso, E.; Luciano, P.; Menna, M.; Esposito, G.; Iuvone, T.; Pala,
D. Eur. J. Org. Chem. 2003, 898–900.
17. Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.; Kita, Y. Tetrahedron 2001,
57, 345–352.
18. Data for 9: Rf (MeOH/CH2Cl2, 1:9) 0.56; IR (ATR) mmax 3462, 2937, 1606, 1442,
1220 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 6.52 (1H, s, H-7), 5.10–5.07 (1H, m, H-
;
References and notes
30), 3.86 (3H, s, OCH3-10), 2.36–2.27 (1H, m, H2-4a), 2.19–2.14 (1H, m, H2-4b),
2.12–2.06 (3H, m, H2-20 and H2-10a), 1.78–1.73 (2H, m, H2-3), 1.67 (1H, m, H2-
10b), 1.66 (3H, s, H3-60), 1.58 (3H, s, H3-50), 1.33 (3H, s, H3-9); 13C NMR (CDCl3,
75 MHz) d 150.6 (C-8), 147.3 (C-6), 138.1 (C-8a), 131.8 (C-40), 124.3 (C-30),
122.0 (C-4a), 108.7 (C-5), 98.2 (C-7), 75.8 (C-2), 56.1 (C-10), 39.9 (C-10), 31.0 (C-
3), 25.8 (C-60), 24.4 (C-9), 22.6 (C-20), 20.8 (C-4), 17.6 (C-50); (+)-HRESIMS
[M+H]+ 551.3367 (calcd for C34H47O6, 551.3347).
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