A high-yielding synthesis of the naturally occurring antitumour agent irisquinone

Article abstract of DOI:10.3390/50100082

A short, high-yielding synthesis of the antitumour agent irisquinone (1) is described. The key steps are the palladium catalysed coupling reaction of dec-9-yn-1-ol with iodide (2) to form alkyne (3) and the Fremy's salt oxidation of phenol (7).

Full text of DOI:10.3390/50100082

Molecules 2000, 5, 82-88
molecules
ISSN 1420-3049
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A High-Yielding Synthesis of the Naturally Occurring
Antitumour Agent Irisquinone
John A. Hadfield1,*, Alan T. McGown1 and John Butler2
1Cancer Research Campaign Section of Drug Development and Imaging, Paterson Institute for Cancer
Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK
E-mail: jhadfield@picr.man.ac.uk
2 Department of Biological Sciences, Salford University, Salford, M5 4WT, UK
*Author to whom correspondence should be addressed.
Received: 2 November 1999 / Accepted: 12 January 2000 / Published: 18 January 2000
Abstract: A short, high-yielding synthesis of the antitumour agent irisquinone (1) is de-
scribed. The key steps are the palladium catalysed coupling reaction of dec-9-yn-1-ol with
iodide (2) to form alkyne (3) and the Fremy’s salt oxidation of phenol (7).
Keywords: Irisquinone; antitumour; Chinese medicine.
Introduction
The seeds of Iris pallasi (Iridaceae) have been used in Chinese folk medicine for the treatment of
various malignancies and for the treatment of metrorrhagia and vaginal discharge [1]. Irisquinone (1)
has been isolated as an active principle [2] from the seed oil of I. pallasi and this 1,4-benzoquinone is
effective against cervical carcinoma, lymphosarcoma, hepatoma and Ehrlich ascites carcinoma (EAC)
in mice [2, 3]. Irisquinone (1) damages nuclei of cells and inhibits [3] mitosis in cancer cells. Respira-
tion of P388 cells is significantly inhibited by irisquinone (1) and mitochondrial damage to EAC cells
has been noted [4]. Furthermore, levels of cyclic guanosine monophosphate have been shown to in-
crease [5] in plasma of tumour bearing mice after treatment with this quinone (1). These results sug-
gest that the antitumour action of irisquinone (1) is likely to be different from that of other cytotoxic
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
agents. There are several syntheses of irisquinone (1) described [6 – 9] in the literature. However the
best yield reported [6] was 25% over seven steps. In order to study its mechanism of action, our labo-
ratories required a good supply of irisquinone (1). Herein is described a short, high-yielding synthesis
of irisquinone (1).
Results and Discussion
Dec-9-yn-1-ol was prepared from commercially available dec-2-yn-1-ol by the acetylene Zipper re-
action [10] and the aryl iodide (2) was prepared by a literature method [11]. Various palladium cata-
lysed coupling reactions of iodide (2) with dec-9-yn-1-ol were tried to optimise the yield of alkyne (3)
using different bases, co-catalysts, solvents and temperatures [12 – 18]. The method of Alami [19] us-
ing 5 mol% Pd(PPh3)4, 10 mol% CuI and piperidine as both base and solvent afforded the alkyne (3) in
98% yield.
O
O
(CH2)8OH
O
O
I
O
O
MeO
MeO
MeO
(CH2)10OH
Pd(PPh3)4/CuI
piperidine
Pd/C, 1,4-cyclohexadiene
2
3
4
TPAP
O
O
OH
O
5
O
MeO
aq. HCl
(CH2)9
(CH2)5Me
MeO
(CH2)9
(CH2)5Me
MeO
(CH2)9CHO
Me(CH2)6PPh3Br
6
7
(KSO3)2NO
O
MeO
(CH2)9
(CH2)5Me
O
1
Scheme 1. Synthesis of irisquinone.
Reduction of this alkyne (3) with 1,4-cyclohexadiene and palladium on carbon using a transfer hy-
drogenation process [20] afforded the fully saturated alcohol (4) in quantitative yield. Swern oxidation
of alcohol (4) using activated DMSO afforded aldehyde (5) in only 21% yield. However, oxidation

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Molecules 2000, 5
with tetrapropylammonium perruthenate (TPAP) [21] afforded the desired aldehyde (5), after column
chromatography on silica in virtually quantitative yield after 10 minutes reaction. This aldehyde (5)
proved to be unstable and was reacted as soon as it was prepared with n-heptyltriphenylphosphonium
bromide. This reaction afforded exclusively the Z-olefin (6) in excellent yield. Removal of the meth-
oxymethyl protecting group from olefin (6) using dilute hydrochloric acid afforded the phenol (7) in
quantitative yield. Salcomine catalysed oxidation of phenols has previously been used [22] to prepare
1,4-benzoquinones. However, in our laboratory, salcomine oxidation of phenol (7) afforded the desired
irisquinone (1) in varying yields of 30-60%. Also oxidation of phenol (7) with molecular oxygen in the
presence of benzyltrimethylammonium hydroxide [23] failed to produce the desired benzoquinone (1)
in satisfactory yield. Fremy’s salt oxidation [24] of this phenol (7), however, produced irisquinone (1)
in excellent yield (87%)(Scheme 1).
The above synthesis of irisquinone (1) was attained from aryl iodide (2) in six steps in an overall
yield of 70%. The general methodology described can be utilised to synthesise a range of alkyl or
alkenyl substituted benzoquinones in excellent yield. The biological activities of irisquinone (1) and
analogues will be reported in a subsequent paper.
Experimental
Synthetic intermediates were used as received from Aldrich Chemical Company or Lancaster Syn-
thesis. NMR spectra were determined on a Bruker AC300 (at 300 MHz) NMR spectrometer in CDCl3
and are expressed in δ values relative to tetramethylsilane. Coupling constants (J) are measured in Hz.
Infra-red spectra were recorded on a Perkin Elmer 1710 FT spectrometer and are expressed in cm-1.
UV-Vis spectra were determined on a Varian Cary 1 UV-VIS spectrophotometer. Melting points are
uncorrected. Electron impact mass spectra were determined using a VG Trio 2 or a Kratos MS25 mass
spectrometer at an ionisation energy of 70 eV.
10-[3’-Methoxy-2’-(methoxymethoxy)phenyl]dec-9-yn-1-ol (3)
To a stirred solution of the aryl iodide (2) (108 mg, 0.367 mmol), copper (I) iodide (10 mol%, 10
mg, 55 µmol), tetrakis(triphenylphosphine) palladium (0) (5 mol%, 20 mg, 17 µmol) in piperidine (1
ml) was added dec-9-yn-1-ol (2.3 eq., 13l mg, 0.85 mmol) in piperidine (1ml) under an atmosphere of
argon. The reaction mixture was shaken vigorously for 5 min, stirred for a further 25 min at room tem-
perature, hydrolysed with saturated aqueous ammonium chloride (10 ml) and extracted with dichlo-
romethane (3 x 10 ml). The combined organic extracts were washed with brine (3 x l0 ml), dried over
anhydrous magnesium sulfate, filtered and concentrated to yield an orange/yellow oil (231 mg). The
crude mixture was eluted on silica gel with petrol:ethyl acetate (7:3) to yield the title alkynol (3) (253
mg, 98%) as a pale orange oil. νmax (film) 3407(OH). δH: 6.90 (2 H, m, Ar-H-4', H-5'); 6.80 (1 H, dd, J
6 and 4, Ar-H-6'); 5.20 (2 H, s, O-CH2-O); 3.80 (3 H, s, Ar-OCH3); 3.60 (3 H, s, -OCH2OCH3); 3.58 (2

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Molecules 2000, 5
H, t, J 7, H-l), 2.40 (2 H, t, J 8, H-8), 1.40 (12 H, m, Hs-2 - 7). m/z (El) 320 (M+, 25%), 277 (25), 262
(25), 183 (40), 81 (60), 69 (100), 55 (40). [Found: m/z 320.1988 (M+). C19H28O4 requires 320.1988]
10-[3’-Methoxy-2’-(methoxymethoxy)phenyl]decan-l-ol (4)
To a stirred solution of the alkynol (3) (3.85 g, 12.0 mmol) in absolute ethanol (50 ml) was added
1,4-cyclohexadiene (20 eq., 23 ml, 240 mmol). The solution was cooled to 0oC and Pd/C 10% (1.2 eq.,
3.85 g, 14 mmol) was added very carefully in small portions. The suspension was stirred under an at-
mosphere of argon at room temperature for 1 h, filtered through Celite and the filtrate concentrated to
yield the title alcohol (4) (3.88 g, 99.8%) as a colourless oil. νmax (film) 3471 (OH). δH: 6.95 (1 H, t, J
8, Ar-H-5'); 6.83 (1 H, dd, J 8 and 2, Ar-H-4'); 6.75 (1 H, dd, J 8 and 2, Ar-H-6'); 5.10 (2 H, s, -OCH2-
O); 4.85 (1 H, s, -OH), 3.80 (3 H, s, Ar-OCH3); 3.55 (3 H, s, -OCH2OCH3); 3.54 (2 H, t, J 7, H-l), 2.65
(2 H, t, J 8, H-10), 1.70-1.20 (16 H, bm, Hs-2 -9). m/z (EI) 324 (M+, 10%) 292 (20), 262 (45), 150
(65), 137 (100), 45(50).
10-[3'-Methoxy-2'-(methoxymethoxy)phenyl]decan-l-al (5)
To a stirred suspension of the alcohol (4) (859 mg, 2.65 mmol), 4-methylmorpholine-N-oxide (1.5
eq., 542 mg, 4.63 mmol) and activated powdered 4A molecular sieves (1.54 g, 500 mg/mmol) in anhy-
drous dichloromethane (7 ml) was added, in one portion, tetrapropylammonium perruthenate (VII), (5
mol%, 54.2 mg, 0.154 mmol). The reaction mixture was stirred under argon for 10 min and filtered
through a short pad of silica eluting with ethyl acetate to yield the title aldehyde (5) (830 mg, 97%) as
a pale yellow oil. νmax (film) 1725 (C=O). δH: 9.67 (1 H, t, J, 3, CHO); 6.95 (1 H, t, J 8, Ar-H-5'); 6.83
(1 H, dd, J 8 and 2, Ar-H-4'); 6.75 (l H, dd, J 8 and 2, Ar-H-6’); 5.10 (2 H, s, -OCH2O); 3.80 (3 H, s,
Ar-OCH3); 3.55 (3 H, s, -OCH2OCH3); 2.65 (2 H, t, J 8, H-10); 2.35 (2 H, m, H-2), 1.60-1.20 (14 H,
bm, Hs-3 - 9). m/z (EI) 322 (M+, 35%) 137 (45), 85 (50), 83 (75), 44 (100).
1-[(Z)Heptadec- l0'-enyl]-3-methoxy-2-(methoxymethoxy)benzene (6)
To a stirred suspension of n-heptyltriphenylphosphonium bromide (2 eq, 548 mg, 1.24 mmol) in
1,4-dioxane (2 ml) was added a solution of potassium t-butoxide (139 mg, 1.24 mmol) in 1,4-dioxane
(l ml) under argon. After 30 min stirring at room temperature, a solution of aldehyde (5) (200 mg, 0.62
mmol) in 1,4-dioxane (0.5 ml) was added. After stirring for a further hour, the solution was quenched
with saturated aqueous ammonium chloride (10 ml). The aqueous solution was extracted with diethyl
ether (3 x 10 ml) and the combined ethereal extracts were washed with water (3 x 10 ml), brine (3 x 10
ml) and dried over anhydrous magnesium sulfate. The solvent was filtered and concentrated to yield a
crude mixture as a brown oil (505 mg). This oil was eluted on silica with hexane:ether (9:1) to yield
the title (Z)-alkene (6) (213 mg, 85%) as a pale brown syrup. δH: 6.95 (1 H, t, J 8, Ar-H-5’); 6.83 (1 H,

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Molecules 2000, 5
dd, J 8 and 2, Ar-H-4’); 6.75 (1 H, dd, J 8 and 2, Ar-H-6’), 5.35 (2 H, t, J 4.7, H-10', H-11'); 5.10 (2 H,
s, -OCH2O); 3.80 (3 H, s, Ar-OCH3); 3.60 (3 H, s, OCH2OCH3); 2.65 (2 H, t, J 8, H-1’); 2.00 (4 H, m,
H-9', H- l 2'); 1.60 (2 H, m, H- l6'); 1.40-1.20 (20 H, bm, Hs-2'-8', H-13', H- 14', 11-15'); 0.90 (3 H, m,
H-17'). m/z (EI) 404 (M+; 20%) 391 (20), 263 (100), 137 (40), 106 (35), 55 (40).
2-[(Z)Heptadec-10'-enyl]-6-methoxyphenol (7)
To a stirred solution of the alkene (6) (483 mg, 1.l9 mmol) in i-propanol/ THF (1:1, 10 ml) was
added 2 M HCl (4 ml). The solution was stirred at room temperature for 1 h and was extracted with
dichloromethane (3 x 25 ml). The combined organic extracts were washed with saturated aqueous so-
dium bicarbonate (3 x 25 ml), brine (3 x 25 ml), dried over anhydrous magnesium sulfate, filtered and
concentrated to yield the title phenol (7) (427 mg, 99.8%) as a colourless oil. νmax (film) 3565 (OH).
δH: 6.80 (3 H, m, Ar-H-3’, H-4’, H-5’); 5.70 (1 H, s, Ar-OH); 5.35 (2 H, t, J 4.7, H-10', H- 1l’); 3.90 (3
H, s, Ar-OCH3); 2.65 (2 H, t, J 8, H-1'); 2.00 (4 H, m, H-9', H-12’); 1.60 (2 H, m, H-16’); 1.40-1.20
(20 H, m, Hs-2'-8', H13', H-14', H-15'); 0.90 (3 H, m, H-17'). m/z (EI) 360 (M+, 35%) 137 (l00).
2-[(Z)Heptadec-10'-enyl]-6-methoxybenzo-1,4-quinone, Irisquinone (1)
To a stirred mixture of NaH2PO4.H2O (7.4 eq., 644 mg, 4.67 mmol) in water (200 ml), containing
Aliquat 336 (1.25 eq, 0.361 ml, 0.79 mmol), was added the phenol (7) (227 mg, 0.631 mmol) in di-
chloromethane (13 ml). Potassium nitrosodisulfonate (Fremy’s salt) (2.5 eq, 423 mg, 1.58 mmol) was
added and the mixture shaken vigorously until a colour change to yellow became permanent. The or-
ganic layer was collected and the aqueous layer extracted with dichloromethane (3 x 5 ml). The com-
bined organic extracts were washed with water (3 x 5 ml), brine (3 x 5 ml), dried over anhydrous mag-
nesium sulfate, filtered and concentrated to yield the crude quinone (213 mg). The product was eluted
on silica gel eluting using petrol:ethyl acetate (3:2) to yield the title quinone (1) (205 mg, 87%) as
yellow crystals from EtOH; m.p. 42-42.5oC (lit. mp [25] 42.5-43.5oC). νmax (film) 1685 (C=O), 1652
(C=O), 1598 (C=C). λmax 267 nm (15,500) and 363 (980). δH: 6.50 (1 H, dt, J 2 and 1, H-3); 5.90 (1
H, d, J 2, H-5); 5.35 (2 H, t, J 4.7, H-10', H-11'); 3.90 (3 H, s, Ar-OCH3); 2.40 (2 H, t, J 7, H-1'); 2.00
(4 H, m, H-9', H-l2'); 1.60 (2 H, m, H-16'); 1.40-1.20 (20 H, m, Hs-2' - 8', H-13', H-14', H-15'); 0.90 (3
H, m, H-17'). (Found: C, 76.94; H, 10.27. C24H38O3 requires C, 76.96; H, 10.23%). m/z (EI) 374 (M+,
40% ) 153 (100), 109 (20).
Acknowledgements: This work was supported by the Cancer Research Campaign and the Medical Re-
search Council (UK). Drs Simon Moore and Xiu-guo Zhang are acknowledged for experimental work
and advice.

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Molecules 2000, 5
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Sample availability: samples are available from the authors.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.