An efficient two-step synthesis of jensenone isolated from Eucalyptus jensenii. Synthesis of analogues and evaluation as antioxidants

Article abstract of DOI:10.1071/CH05061

A phloroglucinol derivative, jensenone (1) isolated from leaves of Eucalyptus jensenii has been synthesized for the first time through a short and efficient two-step procedure starting from commercially available phloroglucinol. The methodology provides a simplified route to introduce diformyl moiety for synthesis of biologically active formylated phloroglucinol compounds such as antimalarial robustadials, cancer chemopreventive euglobals, and antifouling sideroxylonals. Several analogues of jensenone have also been synthesized and evaluated for antioxidant capacity. CSIRO 2005.

Full text of DOI:10.1071/CH05061

Short Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2005, 58, 551–555
An Efficient Two-Step Synthesis of Jensenone Isolated
from Eucalyptus jensenii. Synthesis of Analogues
and Evaluation as Antioxidants
Sandip B. Bharate,A Siddheshwar K. Chauthe,A Kamlesh K. Bhutani,A and Inder P. SinghA,B
A Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER),
SAS Nagar, Punjab 160062, India.
B Corresponding author. Email: ipsingh@niper.ac.in
A phloroglucinol derivative, jensenone (1) isolated from leaves of Eucalyptus jensenii has been synthesized for the
first time through a short and efficient two-step procedure starting from commercially available phloroglucinol. The
methodology provides a simplified route to introduce diformyl moiety for synthesis of biologically active formylated
phloroglucinol compounds such as antimalarial robustadials, cancer chemopreventive euglobals, and antifouling
sideroxylonals. Several analogues of jensenone have also been synthesized and evaluated for antioxidant capacity.
Manuscript received: 24 February 2005.
Final version: 25 May 2005.
Jensenone, 1,3-diformyl-5-(3-methyl-butyryl)-2,4,6-trihyd-
roxybenzene (1), was isolated from the steam-volatile oil of
Eucalyptus jensenni belonging to the family Myrtaceae and
its structure was determined by chemical and spectral meth-
ods in 1992.[1] It has also been reported from E. saligna[2] and
E. apodophylla.[3] It exhibits strong anti-feedant activity[4]
as well as inhibition of photosynthetic electron transport.[1]
Grandinol (2), another naturally occurring analogue, was
shown to possess antibacterial and plant growth regulatory
activity.[5,6] Both jensenone and grandinol are key precursors
for many of the biologically active formylated phlorogluci-
nol compounds found in Eucalyptus. These, Fig. 1, include
sideroxylonals (3, anti-fouling and antimicrobial),[7,8] grand-
inal (4, anti-fouling),[9] robustadials (5, antimalarial),[10]
euglobals (6, Epstein–Barr virus inhibitory),[11,12] and
macrocarpals (7, antibacterial and HIV reverse-transcriptase
inhibitory activity).[13,14] Acylphloroglucinol compounds
such as those isolated from plants of family Guttiferae
and Myrtaceae, for example semimyrtucommulone (8),
are known to exhibit antioxidative properties (Fig. 2).[15]
Reports show that acyl phloroglucinols possess both anti-
and pro-oxidant properties and have been proposed as lead
compounds for treatment of degenerative diseases. These
compounds have a role in the central nervous system as
modulators of neurotransmitters associated with neuronal
damage and depression.[16] Besides, several other simple
phloroglucinol compounds such as hyperjovinol A (9) and
its related compound 10 from Hypericum jovis are reported
to possess antioxidant capacity at the cellular level compa-
rable to the commonly used antioxidant standard ‘trolox’
(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid,
a water-soluble form of vitamin E) thereby providing pro-
tection against reactive oxygen species (ROSs).[17] Garci-
nol (11), another phloroglucinol compound isolated from
Garcinia indica, possesses free radical scavenging activity. It
was suggested that both phenolic groups and β-diketone may
contribute to antioxidant properties.[18]
Structural features of formylated phloroglucinol com-
pounds also suggest their potential as antioxidants and pos-
sible role in chemoprevention of several diseases caused by
free radicals. The free radicals are often generated in biolog-
ical systems in the form of ROSs such as superoxide anion
•
radicals (O−2 ) and singlet oxygen (1O2).[19] These ROSs can
trigger lipid peroxidation as well as oxidation of lipids and
proteins and cause extensive damage to the cells. Oxidative
stress resulting from an imbalance of oxidizing species and
natural antioxidants in the body has been thought to have con-
tributed to ageing, cell apoptosis, and severe diseases such as
cancer, Parkinson’s disease, Alzheimer’s disease, and even
cardiovascular disorders.[20]
Our interest in this work therefore was to synthesize
jensenone, to find a suitable method for diformylation, to
simplify the synthetic route to other biologically impor-
tant formylated/diformylated phloroglucinol compounds,
and to evaluate naturally occurring and synthetic monomeric
phloroglucinol compounds as antioxidants.
The total synthesis of other diformyl phloroglucinol
derivatives such as 3–7 have been reported and in all cases,
the introduction of diformyl moiety onto the phloroglu-
cinol nucleus was achieved in five steps involving the
use of hazardous and expensive chemicals.[21,22] The steps
involved were bromination with benzyltrimethyl ammonium
© CSIRO 2005
10.1071/CH05061
0004-9425/05/070551

552
S. B. Bharate et al.
CHO
OH
CHO
OH
CHO
OH
CHO
OH
HO
O
HO
O
HO
OH
HO
OH
OH
H
CHO
OH
HO
R1
O
OHC
OHC
OHC
CHO
H
H
R2
Sideroxylonals (3):
1 ϭ CHO, R2 ϭ CH2CH(CH3)2
Grandinal (4):
1 ϭ COCH2CH(CH3)2, R2 ϭ H
Robustadials (5)
Euglobal Ia1 (6)
Macrocarpal A (7)
R
R
Fig. 1. Diformylated phloroglucinols derived biogenetically from jensenone.
O
O
O
OH
HO
O
O
O
OH HO
OH HO
OH
HO
OH
O
OH
OH
O
OH
OH
OH
8
9
10
11
Fig. 2. Naturally occurring antioxidant phloroglucinol compounds.
tribromide, lithiation with n-butyl lithium, introduction of
methyl ester moiety by methyl chloroformate, followed by
reduction with DIBAL to give an alcohol, and then oxidation
to yield an aldehyde. The overall yield using the above reac-
tions varies from 25 to 29%.[21,22] We have achieved intro-
duction of diformyl functionality on phloroglucinol nucleus
by a single-step procedure with the application of modified
Duff reaction using inexpensive hexamethylene tetramine in
40% yield.[23,24] Herein, we describe the first synthesis of
jensenone along with several of its analogues for evaluation
as antioxidants.
We have successfully synthesized 1 in two steps start-
ing from commercially available phloroglucinol (12) in
28% overall yield, Scheme 1. The first step involves the
Friedel–Craft acylation of phloroglucinol with isovaleryl
chloride in presence of aluminum chloride as catalyst to yield
1-(3-methyl-butyryl)-2,4,6-trihydroxybenzene (13) in 70%
yield.[25] The next step is introduction of two formyl groups
onto the benzene nucleus. Most of the reported formy-
lation reactions involve electrophilic attack on aromatic
rings to introduce a latent formyl group easily convertible
to a formyl group during work-up or a in few synthetic
steps, for example, formylation using POCl3/DMF or tri-
ethyl orthoformate. The diformylation reaction was found to
be challenging because the introduction of one formyl group
onto an aromatic ring deactivates the phloroglucinol nucleus
towards a second formylation. Several synthetic strategies
exist for diformylation, however, most are low yielding or
involve multistep synthesis. The synthesis of 4-tert-butyl-
2,6-diformyl phenol involves four steps and gives an overall
yield of less than 4%.[26] Similarly, polyformylbenzenes
have been synthesized from 1-methoxy-1,4-cyclohexadienes
underVilsmeier–Haack conditions using 6–8 eq. of DMF and
2.5–4.0 eq. ofPOCl3.[27] Anothermethodinvolvesreactionof
2-hydroxy-3-(hydroxymethyl) benzaldehydes with ethylene
diamine and copper acetate to furnish an intermediate com-
plex. Oxidation followed by acidic hydrolysis of the complex
yields diformylated compounds.[28]
Several reactions and different experimental conditions
were tried to achieve diformylation of 13 to obtain jensenone.
As shown in Table 1, treatment of 13 with 1 eq. of
POCl3/DMF resulted in exclusive formation of mono-
formylated product in 70% yield. Reaction using 5 eq. of
POCl3/DMF gave mono and diformylated products in a 9:1
ratio. Similarly, reaction with 1, 2, and 5 eq. of triethylortho-
formate resulted in exclusive formation of monoformylated
product. The most exciting and striking results were obtained
with modified Duff reaction.[23,24] Reflux of 13 with 2 eq.
of hexamethylene tetramine in trifluoroacetic acid (TFA) for
20 h at 70◦C resulted in exclusive formation of diformylated
product 1 in 40% yield. However, using 1 eq. of hexamethy-
lene tetramine resulted in mono and diformylated products
in an 8:2 ratio. The mechanism involved in the modi-
fied Duff reaction has been proposed, that involves initial
aminoalkylation followed by dehydrogenation and hydrol-
1
ysis to yield diformylated product 1.[29] The H NMR of
compound 1 showed characteristic peaks at δH 10.14 and
10.19, accounting for two formyl groups. Compound 1 was
confirmed by co-TLC with an authentic sample. The IR,
1H NMR, and 13C NMR data were completely identical
with those reported for jensenone. The synthetic sample
showed a melting point of 100–102◦C (lit. 102◦C) and
was undepressed on admixture with an authentic natural
sample.[1]

Two-Step Synthesis of Jensenone, its Analogues, and Evaluation as Antioxidants
553
CHO
HO
OH
HO
OH
O
HO
OH
O
(a)
(b)
R
OHC
OH
OH
OH
1
12
13: R ϭ CH2CH(CH3)2
22: R ϭ CH3
23: R ϭ CH2CH3
(e, b)
(c)
R1
HO
R1
OH
CHO
OH
CHO
OH
HO
HO
OH
O
(d)
R
OH
R
H3C
OH
O
19: R1 ϭ R2 ϭ H
16: R1 ϭ R2 ϭ CHO
18: R ϭ CH2CH(CH3)2
24: R ϭ CH3
2: R ϭ CH2CH(CH3)2
14: R ϭ CH3
25: R ϭ CH2CH3
15: R ϭ CH2CH3
Scheme 1. Reagents and conditions: (a) RCOCl, AlCl3, 50◦C, 70%; (b) (CH2)6N4, TFA, 70◦C, 40%; (c) POCl3,
DMF, room temp., 70%; (d) CH3I, KOH, MeOH, 70◦C, 50%; (e) (CH3)2CHCH2CH2CH2I, KOH, MeOH, 65◦C, 45%.
Table 1. Reagents for synthesis of mono- and di-formylated phloroglucinol derivatives
Reagent(s)
Conditions
RatioA mono:di
Yield [%]A
POCl3/DMF (1 eq. each)
POCl3/DMF (1 eq. each)
POCl3/DMF (2 eq. each)
POCl3/DMF (2 eq. each)
POCl3/DMF (5 eq. each)
POCl3/DMF (5 eq. each)
CH(OC2H5)3 (1 eq.)
CH(OC2H5)3 (2 eq.)
CH(OC2H5)3 (5 eq.)
(CH2)6N4 (1 eq.)/TFA
(CH2)6N4 (2 eq.)/TFA
Room temp., 1 h
Room temp., 5–10 h
Room temp., 1 h
Room temp., 5–10 h
Room temp., 1 h
Room temp., 5–10 h
Room temp., 1 h
Room temp., 1 h
Room temp., 1 h
70◦C, 5–20 h
100:0
100:0
100:0
100:0
90:10
90:10
100:0
100:0
100:0
80:20
0:100
70
50
70
50
70
50
50
50
40
50
40
70◦C, 5–20 h
A Yields obtained after chromatographic isolation.
Monoformyl analogues of 1 such as grandinol (2), 14, and
15 were synthesized by reported methods in 17–20% overall
yield as depicted in Scheme 1.[25] Diformyl analogues of 1,
compounds 16 and 17, in which the isovaleryl moiety has
been replaced by isopentyl and methyl group respectively
have also been synthesized in three steps (Schemes 1 and
2).[30] All the analogues were characterized by comparison
with literature data.[25]
The antioxidant capacity of all the synthesized compounds
was measured in terms of inhibition of lipid peroxidation and
free radical scavenging capacity. Lipid peroxidation studies
are done using a lipid auto-oxidation model, in which tissue
from animals or linoleic acid itself can be used as a lipid
source. Linoleic acid as an oxidation substrate simplifies the
assay, rendering it more reproducible than the assays in which
lipids from a biological source are used. Oxidation of linoleic
acid leads to formation of conjugated diene peroxides, and
it has been reported that the catechols, hydroquinones, and
other phenolics react with these peroxy radicals to form o/p-
quinones.[31]
Lipid peroxidation has been determined by two methods,
the ferric thiocyanate (FTC) method and the thiobarbituric
acid (TBA) method. The FTC test[32] determines the amount
of peroxide produced at the initial stage of lipid peroxi-
dation whereas the TBA test[33] measures the amount of
malondialdehyde (MDA) produced after the decomposition
of the lipid peroxide during the oxidation process. In both the
assays, a lower absorbance as compared to control indicates
a higher level of antioxidant capacity and the results were
expressed as percentage inhibition as obtained from the
absorbance readings on final (fifth) day of incubation, as
shown in Table 2.
The free radical scavenging capacity has been deter-
mined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay,[34]

554
S. B. Bharate et al.
CHO
OH
HO
OH
HO
OH
HO
OH
HO
(a)
(b)
(c)
OHC
H3C
H3C
CHO
OH
OH
OH
OH
12
20
21
17
Scheme 2. Reagents and conditions: (a) POCl3, DMF, room temp., 70%; (b) NaBH3CN, THF, room temp., 60%; (c) (CH2)6N4, TFA, 70◦C, 40%.
Table 2. Antioxidant capacity of natural and synthetic
phloroglucinols
diformylation can be conveniently achieved in last step. The
results from biological evaluation suggest that phloroglucinol
molecules having free hydroxyl groups have higher antiox-
idant capacity, whereas those containing phenolic groups
hydrogen-bonded to formyl or acyl groups showed consid-
erably less antioxidant capacity.
Sample
FTC assay
TBA assay
DPPH assay
inhibition [%]A,B inhibition [%]A,B EC50 [µM]C
Trolox
19
21
Ascorbic acid
2
14
15
17
16
1
76.7
73.1
72.1
62.7
21.9
21.5
20.4
16.0
15.8
12.9
0
72.0
70.8
71.4
53.1
25.9
25.7
26.1
21.3
21.8
0.23
0.24
0.26
0.68
2.10
2.18
2.08
2.50
2.40
Experimental
Synthesis of 1
A solution of phloroglucinol (12) (1 g, 7.99 mmol) and anhydrous
AlCl3 (3.17 g, 23.74 mmol) in CS2 (10 mL) and nitrobenzene (15 mL)
was stirred at room temperature for 20 min. After addition of iso-
valeryl chloride (2.9 mL, 23.74 mmol) at 50◦C, the reaction mixture
was further stirred for 30 min. Nitrobenzene was removed under
reduced pressure and crude reaction mixture was purified by silica
gel column chromatography (1/1 ethyl acetate/hexane) to yield 13
as a yellow solid (1.16 g, 70%) which was identified by compari-
son of spectral data with literature values.[25] A solution of 13 (1 g,
4.76 mmol) and hexamethylene tetramine (2 g, 14.28 mmol) in anhy-
drous trifluoroacetic acid (10 mL) was refluxed for 20 h.[24] Reaction
mixture was then poured into 4 N HCl and extracted with ethyl
acetate. The organic layer was washed with brine solution and dried
over anhydrous Na2SO4. The crude product was purified by silica
gel column chromatography (30% ethyl acetate in hexane) to yield
1 as white crystalline solid (0.5 g, 40%). mp 100–102◦C. IR (KBr)
νmax/cm−1 3432, 2952, 1610, 1192. δH (CDCl3, 300 MHz) 15.10
(s, 1H), 14.10 (s, 1H), 10.16 (s, 1H), 10.12 (s, 1H), 2.99 (d, J 6.4, 2H),
2.25 (m, 1H), 0.99 (d, J 6.3, 6H). EI-MS m/z 266 [M+].[1]
7.10
0
19.0
—
Control
A Calculated from the obsorbance reading on the fifth day of incubation.
B
Inhibiton = [(Acontrol − Asample)/Acontrol] × 100.
C Concentration of sample at which 50% decolouration of DPPH
solution has been observed.
which is based on the measurement of the scavenging ability
of antioxidants towards the stable radical 2,2-diphenyl-1-
picrylhydrazyl (DPPH). This assay involves a fast electron-
transfer process from phenoxide anions to the DPPH free
radical. Hydrogen atom abstraction from the neutralArOH by
DPPH occurs very slowly in strong hydrogen bond accepting
solvents such as methanol and ethanol. The DPPH free radi-
cal is reduced to the corresponding hydrazine when it reacts
with hydrogen donors, and the extent of reaction depends
on hydrogen donating ability of the antioxidant. The radical
scavengingcapacityhasbeenmentionedintermsofEC50 (the
concentration at which 50% decolouration of DPPH solution
indicated by decrease in absorbance at 520 nm) as shown in
Table 2.
FromtheresultsobtainedinFTCandTBAtest(asdepicted
in Table 2), it was observed that the compounds 19 and 21
showed higher activity compared to other analogues. The
activity of 19 and 21 was comparable to trolox and ascorbic
acid, whereas the remainder of the synthetic acylphloroglu-
cinols, along with natural products jensenone and grandinol,
showed considerably lower antioxidant capacities.The results
obtained from the DPPH assay strongly correlated with FTC
and TBA results.
FTC Method
30 µL of sample solution (5 mg mL−1) was added to the mixture of
680 µL of 2.51% linoleic acid solution in ethanol and 2.25 mL of 40 mM
phosphate buffer (pH 7.0). The mixture was incubated at 40◦C in con-
stant temperature oven. After every 24 h during incubation for 5 d, a
20 µL aliquot was taken from the mixture and diluted with 2 mL of
ethanol followed by the addition of 20 µL of 30% ammonium thio-
cyanate and 20 µL of 20 mM FeCl2 in 3.5% HCl, and exactly after
5 min the absorbance for the red colour was measured at 500 nm. The
level of lipid peroxidation inhibition by each sample was calculated
from absorbance ratio to that of control without any sample. The results
reported are for absorbance on fifth day.[32]
TBA Method
The samples prepared for FTC method were used for this assay. After
incubation for 5 days, 250 µL of the sample solution was taken from the
mixture and 500 µL of 10% aqueous trichloroacetic acid and 500 µL
of 0.8% aqueous thiobarbituric acid solution were added. The mix-
ture was placed in a boiling water bath for 10 min. After cooling, it
was centrifuged at 3000 rpm for 30 min, and the absorbance of the
supernatant was measured at 532 nm.[33]
In conclusion, we have reported first total synthesis
of jensenone that is short and efficient and may have
implications in the study of biosynthetic pathways of nat-
urally occurring phloroglucinol compounds. Further, it will
help improving the synthetic routes for biologically active
sideroxylonals, grandinal, robustadials, and euglobals, where
DPPH Method
DPPH was dissolved in methanol (40 µg mL−1) and sonicated for
15 min to obtain the stable free radical DPPH. Methanolic solutions of

Two-Step Synthesis of Jensenone, its Analogues, and Evaluation as Antioxidants
555
various concentrations of test compounds were added to DPPH solution.
After mixing gently and leaving for 30 min at room temperature, the
absorbance was measured at 520 nm using a UV-vis spectrophotometer.
The free radical scavenging capacity of each sample was determined by
comparing its absorbance with that of blank solution. Ascorbic acid and
trolox were used as standard.[34]
[13] M. Murata,Y.Yamakoshi, S. Homma, K.Aida, K. Hori,Y. Ohashi,
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[16] L. Verotta, Phytochem. Rev. 2002, 1, 389. doi:10.1023/
A:1026069624278
Acknowledgements
S.B.B. is thankful to NIPER for a fellowship. The authors are
thankful to Prof. Hideo Etoh, Shizuoka University, Japan, for
providing an authentic sample of jensenone.
[17] K. Athanasas, P. Magiatis, N. Fokialakis, A. L. Skaltsounis,
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