Total synthesis of s (+)-curcuphenol, s (+)-curcuquinone and s (+)-curcuhydroquinone

Article abstract of DOI:10.14233/ajchem.2016.19475

A synthesis of (-)-curcuphenol, (-)-curcuquinone and (-)-curcuhydroquinone from o-valerolactone is described. The key steps include an Evans asymmetric methylation of 5-(benzyloxy)pentanoic acid (5), an oxidative aromatization of enone (11) and a regioselective oxidation of the phenol to o-quinone derivative with bis(trifluoro acetate)iodobenzene.

Full text of DOI:10.14233/ajchem.2016.19475

Asian Journal of Chemistry; Vol. 28, No. 4 (2016), 771-778
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19475
Total Synthesis of S (+)-Curcuphenol, S (+)-Curcuquinone and S (+)-Curcuhydroquinone
1,*
2
1
RAMAKOTESWARA RAO CHINTA , V. HARIKRISHNA , VIJAYA KUMAR TULAM ,
1
1
2
NAVEEN KUMAR BEJJANKI ,PRATHAMA S. MAINKAR and P.K. DUBEY
1Evolva Biotech Private Limited, TICEL Bio Park Limited, Taramani, Chennai-600 113, India
2Department of Chemistry, JNTUH College of Engineering, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-
500 085, India
*Corresponding author: Tel/Fax: +91 44 42971050/60; E-mail: rkrao983@gmail.com
Received: 14 July 2015;
Accepted: 14 August 2015;
Published online: 30 December 2015;
AJC-17689
A synthesis of (-)-curcuphenol, (-)-curcuquinone and (-)-curcuhydroquinone from o-valerolactone is described. The key steps include an
Evans asymmetric methylation of 5-(benzyloxy)pentanoic acid (5), an oxidative aromatization of enone (11) and a regioselective oxidation
of the phenol to o-quinone derivative with bis(trifluoro acetate)iodobenzene.
Keywords: Evans asymmetric methylation, Robinson annulation, [1,3]-Oxidative rearrangement.
OH
O
OH
INTRODUCTION
Naturally occurring (-)-curcuphenol, (-)-curcuquinone and
(-)-curcuhydroquinone are similar type of phenolic sesquiter-
penes of the bisabolane family [1] (Fig. 1), isolated from the
Caribbean gorgonian Pseudopterogorgia rigid [2] and exhibit
potent antibacterial activity towards Staphylococcus aureus
and the marine pathogen Vibro anguillarum [2a]. These popular
synthetic targets [3]used for the synthesis of heliannuols [4].
The noteworthy of its monocarbocyclic skeleton structure has
resulted in considerable attention from the synthetic community
[3-6].
To date, only few syntheses of (-)-curcuphenol, (-)-curcuqui-
none and (-)-curcuhydroquinone have been reported. Despite
these different approaches, none has revealed accessibility of
oxidative aromatization. Thus, our group has focused on the
asymmetric synthetic route of common key intermediate.
O
OH
(-)-Curcuphenol
(-)-Curcuquinone
(-)-Curcuhydroquinone
Fig. 1. Examples of some aromatic bisabolene sesquiterpene
Synthesis
5-(Benzyloxy)pentanoic acid (5): To a stirred solution
of δ-valerolactone (4) (21 g, 210 mmol,) in toluene (200 mL),
KOH (47 g, 840 mmol) and benzyl chloride (72 g, 420 mmol,)
were added and the mixture was stirred at 120 °C overnight,
then cooled to room temperature and treated with 0.5 N HCl
(300 mL) solution to adjust pH to 2. The resulting mixture
was extracted with diethylether (4 × 200 mL) and the organic
phase was washed with brine (100 mL), dried over Na2SO4
and concentrated in vacuo, purification on column chromato-
graphy using silica gel (60-100 mesh), with 30 % AcOEt in
hexane to afforded 21.1 g of desired product 5 in 49 % yield
as a colourless oil; IR (neat, cm-1): 3447, 2929, 1708, 1211,
EXPERIMENTAL
All the chemicals employed in this study were procured
from SigmaAldrich. In present study, all the synthetic reactions
were monitored by TLC. All the synthesized compounds were
confirmed by different spectroscopic methods. The IR spectra
were recorded using KBr pellets on a Perkin Elmer IR spectro-
1
743, 698; H NMR (300 MHz, CDCl3): δ 8.2 (m, 1H), 7.25
(m, 5H), 4.46(s, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.36 (t, J = 6.8
Hz, 2H), 1.78-1.60 (m, 4H); 13C NMR (75 MHz, CDCl3);
HRMS (ESI): Calculated for C12H16O3Na (M++Na) 231.0997,
found 231.1005.
1
photometer. HNMR spectra were recorded on Brucker 300
MHzAvance NMR spectrophotometer using CdCl3 as solvent
and TMS as internal standard (chemical shifts in δ ppm). The
Mass spectra were recorded on Agilent 6300 series ion trap.
(S)-4-Benzyl-3-[5-(benzyloxy)pentanoyl]oxazolidin-2-
one (6): To the stirred solution of carboxylic acid 5 (13.5 g,

772 Chinta et al.
Asian J. Chem.
27 mmol) in dry THF, triethylamine (16.6 mL, 157.7 mmol)
and pivallyl chloride (8.6 mL, 70 mmol) were added at -20 °C
and stirred for 1 h. Then LiCl (4.0 g, 94.2 mmol) was added
and after 10 min and (S or R)-oxazolidinone (11g, 62.8 mmol)
was also added and continued for another 1 h at -20 °C. The
mixture was warmed to 0 °C over a period of 2 h. The reaction
was quenched with NH4Cl solution and with EtOAc (3 × 100
mL). The organic phase washed with water, brine, dried over
Na2SO4 and concentrated in vacuo. purification on column
chromatography using silica gel (60-100 mesh), with 10 %
AcOEt in hexane to afforded auxiliary product 20 g with 85 %
yield; IR (neat, cm-1): 2926, 1779, 1699, 1209, 1100, 750,
700; 1H NMR (300 MHz, CDCl3): δ 7.34-7.15 (m, 10H), 4.57
(m, 1H), 4.48 (s, 2H), 4.09 (d, J = 5.0 Hz, 2H), 3.50 (t, J = 6.0
Hz, 2H), 3.28 (dd, J = 12.8, 3.0 Hz, 1H), 3.03-2.84 (m, 2H),
2.66 (m, 1H), 1.84-1.64 (m, 4H). HRMS (ESI): Calculated
m/z for C22H25O4NNa (M+ +Na) 390.1681, found 390.1696.
4-Benzyl-3-[5-(benzyloxy)-2-methylpentanoyl]oxazo-
lidin-2-one (7): To the stirred solution of auxiliary compound
(20 g, 54 mmol) in dry THF was added 1 M solution of NaHMDS
(5.8 mL, 58 mmol) at -78 °C and stirred for 1h. Then CH3I
(16.8 mL, 270 mmol) was added and the stirring was continued
for 0.5 h and the mixture was allowed to warm ambient tempe-
rature. Upon completion of reaction, the resulting mixture was
quenched with NH4Cl solution and extracted with Et2O (3 ×
150 mL). The organic phase washed with water, brine, dried
over Na2SO4 and concentrated in vacuo. purification on column
chromatography using silica gel (60-100 mesh), with 10 %
AcOEt in hexane to afforded (4S)-4-benzyl-3-[(2S)-5-
(benzyloxy)-2-methylpentanoyl]-1,3-oxazolan-2-one (11.4 g)
with 55 %yield as pale yellow oily liquid; [α]D 34.1: + 8.5 (c =
0.55, CHCl3). IR (neat, cm-1): 2928, 1778, 1696, 1452, 1203,
(7.5 mL, 107 mmol) in anhydrousCH2Cl2 (50 mL) at -78 °C.
The mixture was stirred at same temperature for 15 min. To
this mixture was added dropwise a solution of primary alcohol
(10.5 g, 49 mmol) in anhydrous CH2Cl2 (100 mL) and stirring
was continued at -78 °C for further 1 h. The reaction was
quenched by addition of Et3N (68 mL, 490 mmol) at –78 °C.
The mixture was allowed to warm to ambient temperature and
stirring was continued for 40 min. After addition of water, the
layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 200 mL). The combined organic layers were
washed with water, brine and dried over anhydrous Na2SO4.
Removal of solvent followed by rapid chromatography of the
resulting residue furnished unstable aldehyde as a colourless
liquid and it directly used for next step.
To the solution of methyltriphenyl phosphonium iodide
(63 g, 156 mmol) was added 1.6 M n-BuLi (48.5 mL, 78 mmol)
in anhydrous THF (200 mL) and allowed to stir at room tempe-
rature under inert atmosphere for 3 h. Then the stirring was
stopped and allowed to settle down the solid. The clear super-
natant orange-yellow liquid was transferred into the solution
of above crude aldehyde in dry THF (200 mL) at -78 °C. The
reaction mixture was stirred -78 °C for another 3 h and then
slowly allowed to warm to ambient temperature. Then the reaction
was quenched with crushed ice and the mixture was extracted
with EtOAc (3 × 50 mL). The combined organic layers were
dried over anhydrous Na2SO4. Removal of solvent followed
by purification on column chromatography using silica gel (60-
100 mesh), with 5 % AcOEt in hexane to afforded olefin com-
pound 7 (8.0 g, 90 %) as a pale yellow syrup; IR (neat, cm-1):
1
2930, 1493, 1104, 735, 696; H NMR (300 MHz, CDCl3): δ
7.32-7.19 (m, 5H), 5.64 (m, 1H), 4.96-4.86 (m, 2H) 4.46 (s,
2H), 3.41 ((t, J = 6.6 Hz, 2H), 2.1 (m, 1H), 1.64-1.51 (m, 2H),
1.44-1.30 (m, 3H), 0.99 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 144.5, 138.7, 128.3, 127.6, 127.5, 125.5, 112.7, 72.8,
70.5, 37.7, 33.0, 27.5, 20.2; HRMS (ESI): m/z 227 (M++ Na).
6-(Benzyloxy)-3-methylhexanal (9): A solid of 9-BBN
dimer (10.7g, 44.1 mmol) in dry THF (120 mL) was stirred
for 1 h at 0 °C. Then the solution of olefin compound (15 g,
73.5 mmol) taken in dry THF (50 mL) was added to the reaction
mixture slowly at 0 °C and stirring was continued for again
1 h. The reaction mixture was warmed to ambient temperature
and stirred for overnight. The reaction mixture was cooled to
0 °C and then, 20 % solution of NaOH (22 mL), followed by
aqueous 30 % H2O2 solution (13 mL) were added and the
reaction mixture was stirred again another 12 h at ambient
temperature.After completion of the reaction, the aqueous layer
was extracted with diethyl ether (3 × 150 mL). The combined
organic layers were dried over anhydrous Na2SO4. Evaporation
of the solvent followed by purification on column chromato-
graphy using silica gel (60-100 mesh), with 5 % AcOEt in
hexane to afforded primary alcohol (11.4 g, 70 %) as a
colourless liquid; IR (neat, cm-1): 3400, 2930, 1454, 1099,
734, 698; 1H NMR(300 MHz, CDCl3): δ 7.36-7.24 (m, 5H),
4.47 (s, 2H), 3.46-3.34 (m, 4H), 1.85-1.38 (s, 7H), 0.94 (d, J
= 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 138.3, 128.7,
127.4, 127.3, 72.8, 71.7, 60.8, 39.4, 33.2, 29.1, 27.0, 19.4;
HRMS (ESI): m/z 222 (M+).
1
1101, 1019, 739, 698 cm-1; H NMR (300 MHz, CDCl3): δ
7.36-7.16 (m, 10H), 4.57 (m, 1H), 4.45 (s, 2H), 4.14-3.97 (m,
2H), 3.72 (m, 1H), 3.51-3.41 (m, 2H), 3.26 (dd, J = 12.8, 3.0
Hz, 1H), 2.69 (dd, J = 13.5, 9.8 Hz, 1H), 1.83 (m, 1H), 1.69-
1.59 (m, 2H), 1.53 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H); HRMS
(ESI): m/z 420 (M++ K)
[(4-Methylhex-5-enyloxy)methyl]benzene (8): To the
stirred solution of methylated auxillary compound (10 g, 26
mmol) in MeOH (100 mL) was added NaBH4 (3.0 g, 78 mmol)
in portions at 0 °C and stirring was continued under inert
atmosphere for 2 h. Then, the reaction mixture was quenched
with saturated NH4Cl solution and removed the solvent under
reduced pressure. The residue was extracted with EtOAc (3 ×
100 mL). The combined organic layers were washed with
water, brine and dried with Na2SO4. Removal of the solvent
followed by purification on purification on column chromato-
graphy using silica gel (60-100 mesh), with 10 % AcOEt in
hexane to afforded pure (S)-5-(benzyloxy)-2-methylpentan-
1-ol (4.6 g, 85 %) as colourless liquid; [α]D 25: +31.0 (c 0.1,
CHCl3; IR (neat, cm-1) 3449, 1457, 1009; 1H NMR (300 MHz,
CDCl3): δ 7.36-7.21 (m, 5H), 4.48 (s, 2H), 3.48-3.36 (m, 4H),
1.73-1.42 (s, 5H), 0.91 (d, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 138.4, 128.3, 127.6, 72.9, 70.6, 67.9, 35.5,
29.5, 27.0, 16.5; HRMS (ESI): Calculated m/z for C13H20O2Na
(M+ + Na) 231.1360, found 231.1362;
To a stirred solution of oxalyl chloride (8.45 mL, 98 mmol)
in anhydrous CH2Cl2 (250 mL) was added dropwise DMSO
To a stirred solution of oxalyl chloride (19.4 mL, 226.2
mmol) in anhydrous CH2Cl2 (300 mL) was added dropwise

Vol. 28, No. 4 (2016)
Total Synthesis of S (+)-Curcuphenol, S (+)-Curcuquinone and S (+)-Curcuhydroquinone 773
DMSO (17.5 mL, 248 mmol) inanhydrous CH2Cl2 (100 mL)
at -78 °C. The mixture was stirred at same temperature for 15
min. To this mixture was added dropwise a solution of primary
alcohol (25g, 113.1 mmol) in anhydrous CH2Cl2 (100 mL) and
stirring was continued at -78 °C for further 1 h. The reaction
was quenched by addition of Et3N (78.6 mL, 565.5 mmol) at
-78 °C. The mixture was allowed to warm to ambient tempe-
rature and stirring was continued for 40 min. After addition of
water, the layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 150 mL). The combined organic
layers were washed with water, brine and dried (Na2SO4).
Removal of solvent followed by rapid chromatography of the
resulting residue on silica gel with (60-100 mesh, EtOAc-
hexane 85:15) furnished unstable aldehyde with quantitative
yield as colourless oil.
4-[(S)-5-(Benzyloxy)pentan-2-yl]cyclohex-2-enone
(10): To a stirred solution of primary aldehyde product in
CH3CN (400 mL), methyl vinyl ketone (13.9 mL, 169 mmol)
and tri methyl silyl diethyl amine (TMSEt2N) (2.1 mL, 11.3
mmol) were added under inert atmosphere at ambient tempe-
rature. The reaction mixture was refluxed for 48 h and then
the reaction mixture was cooled to ambient temperature. The
reaction mixture was concentrated under reduced pressure.
The resulted residue was diluted with EtOAc and was also
added H2O. The mixture was extracted with EtOAc (3 × 120
mL). The combined organic layers were washed with water,
brine and dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica
41.5, 40.9, 37.4, 36.3, 27.6, 25.7, 23.8; HRMS (ESI):
Calculated m/z for C18H24O2Na (M+ +Na) 295.1673, found
295.1687;
6-[(S)-5-Hydroxypentan-2-yl]-3-methylcyclohex-2-
enone (11): To the stirred solution of activated Mg turnings
(2.7 g, 111 mmol) in dry Et2O (150 mL) was added CH3I (6.95
mL, 111 mmol) dropwise at 0 °C under inert atmosphere and
stirring was continued for another 2 h. To this generated CH3MgI
was added α,β-unsaturated compound (10 g, 37 mmol) very
slowly drop wise at 0 °C under inert atmosphere. The reaction
mixture was warmed to ambient temperature and stirring was
continued for 12 h. The reaction was quenched with saturated
NH4Cl solution drop wise at 0 °C. The mixture was extracted
with EtOAc (3 × 100 mL) and filtered. The combined organic
layers were washed with water, brine and dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel (60-100 mesh) 15 % EtOAc-
hexane as eluent to give the diastereomeric mixture of Grignard
product (7.7 g, 72 %) as colourless oil; [α]D35.2: 6.0 (c =0.5,
CHCl3): IR (neat, cm-1): 3409, 2931, 1646, 1454, 1108, 738,
697; 1H NMR (300 MHz, CDCl3): δ 7.34-7.18 (m, 5H), 5.62-
5.44 (m, 2H), 4.46 (s, 2H), 3.41 (t, J = 6.8 Hz, 2H), 2.09 (m,
1H), 1.84 (m, 1H), 1.74-1.29 (m, 6H), 1.27-1.15 (m, 5H), 0.88-
0.81 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 138.5, 134.6,
131.7, 130.5, 128.2, 127.5, 72.7, 70.5, 69.6, 39.9, 38.0, 36.4,
30.3, 28.3, 24.0, 22.2; HRMS (ESI): Calculated m/z for
C19H28O2Na (M+ + Na) 311.1987, found 311.1978.
To a well stirred solution of Grignard compound (4 g,
13.9 mmol) in dry CH2Cl2 (100 mL) was added pyridinium
chlorochromate (PCC) (9.0 g, 41.7 mmol) under inert atmos-
phere at 0 °C. The reaction mixture was warmed to ambient
temperature and stirring was continued for 3 h. When the
reaction was complete, the reaction mixture was extracted with
Et2O (5 × 100 mL). The resultant solids were removed by
filtration using celite pad and then washed with Et2O (2 × 100
mL). The combined organic filtrate and washings were washed
with 5 % NaOH, diluted HCl and saturated NaHCO3 aqueous
solutions respectively. Then the organic extract was washed
with water, brine and dried over anhydrous Na2SO4.Removal
of the solvent followed by purification on silica gel (60-100
mesh) 15 % EtOAc-hexane as eluent to give product 11 (2.9
g, 70 %) with [1:1] diastereomeric mixture as colourless oil,
[α]D34.5: - 17.8 (c = 0.5, CHCl3): IR (neat, cm-1): 2932, 1664,
gel (60-100 mesh) 10 % EtOAc-hexane as eluent to give Michael
36.1
addition product (22.9 g, 70 %) as pale yellow oil; [α]D
:
-12.2 (c = 0.5, CHCl3): IR (neat, cm-1): 1790, 1677, 2925,
1454, 1101, 743, 699; H NMR (300 MHz, CDCl3): δ 9.57
1
(m, 1H), 7.31-7.22 (m, 5H), 4.46 (s, 2H), 3.46-3.40 (m, 2H),
2.55-2.29 (m, 2H), 2.09 (s, 3H), 1.82 (m, 1H), 1.61-1.45 (m,
2H), 1.00-0.87 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 208.2,
205.6, 135.7, 128.1, 127.1, 127.0, 73.1, 70.5, 55.9, 42.1, 34.2,
32.5, 31.3, 29.8, 27.4, 17.8; HRMS (ESI): Calculated m/z for
C18H26O3Na (M+ +Na) 313.1779, found 313.1785;
To a stirred solution of Michael addition compound (15
g, 51.7 mmol) in THF (100 mL) were added Bu4NOH (4 mL),
diethyl ether (300 mL) and also 5 % KOH (aq) solution (150
mL), respectively. The resulting reaction mixture was stirred
under inert atmosphere at ambient temperature for 10 min.
After that the reaction mixture was refluxed with vigorous
stirring for 8 h and then the reaction mixture was cooled to
ambient temperature. The reaction mixture was concentrated
under reduced pressure. The residue with aqueous layer was
extracted with EtOAc (3 × 150 mL). The combined organic
layers were washed with water, brine and dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel (60-100 mesh) 5 % EtOAc-
hexane as eluent to give α,β-unsaturated enone 9 (11.3 g, 80 %
yield) as colourless liquid; [α]D 34.1: - 2.2 (c =0.55, CHCl3): IR
(neat, cm-1): 2933, 1715, 1453, 1100, 739, 698; 1H NMR (300
MHz, CDCl3): δ 7.34-7.20 (m, 5H), 6.79 (t, J = 12.6 Hz, 1H),
5.98 (d, J = 10.2 Hz, 1H), 4.46 (s, 2H), 3.43 (t, J = 5.8 Hz,
2H), 2.54-2.22 (m, 3H), 1.94 (m, 1H), 1.59-1.43 (m, 3H), 1.36-
1.21 (m, 2H), 0.96-0.88 (m, 3H); 13C NMR (75 MHz, CDCl3):
δ 199.9, 155.1, 138.3, 129.5, 128.2, 127.5, 127.4, 72.8, 70.2,
1
1451, 1101, 742, 697 cm-1; H NMR(300 MHz, CDCl3): δ
7.34-7.20 (m, 5H), 5.85 (s, 1H), 4.47 (s, 2H), 3.47-3.41 (t,
2H), 2.34-2.24 (m, 3H), 2.17-2.06 (m, 1H), 1.94 (s, 3H), 1.85-
1.70 (m, 1H), 1.70-1.47 (m, 2H), 1.39-1.21 (m, 3H), 0.93 (d,
J = 6.8 Hz, 1H), 0.79 (d, J = 6.8 Hz, 2H); 13C NMR (75 MHz,
CDCl3): δ 200.8, 161.1, 160.9, 138.5, 128.2, 127.5, 126.9,
126.8, 72.8, 70.6, 51.1, 49.7, 30.9, 30.7, 30.3, 29.5, 27.6, 23.3,
22.2, 17.3, 15.5; HRMS (ESI): Calculated m/z for C19H26O2Na
(M+ +Na) 309.1830, found 309.1822.
(S)-1-[5-(Benzyloxy)pentan-2-yl]-2-methoxy-4-methyl-
benzene (16): To a stirred solution of enone 11 (300 mg, 1.1
mmol) was added molecular iodine (838 mg, 3.3 mmol) in
anhydrous MeOH (10 mL) at ambient temperature under inert
atmosphere. The reaction mixture was heated under reflux for
14 h. When the reaction was completed, the reaction mixture
was cooled to ambient temperature and solvent was removed

774 Chinta et al.
Asian J. Chem.
under reduced pressure. The residue was extracted with CHCl3
(3 × 50 mL). The combined organic layers were quenched
with sodium thiosulfate and then washed with water, brine
and dried over anhydrous Na2SO4. Removal of the solvent
followed by purification on column chromatography using
silica gel silica gel (60-100 mesh) 10 % EtOAc-hexane as
eluent to give aromatic product compound (219 mg, 60 %) as
pale yellow syrupy liquid; IR (neat, cm-1): 2932, 1459, 1100,
810, 764; 1H NMR (300 MHz, CDCl3): δ 7.31-7.21 (m, 5H),
6.97 (d, J = 8.08 Hz, 1H), 6.66 (d, 1H), 6.58 (s, 1H), 4.42 (s,
2H), 3.77 (s, 3H), 3.39 (t, J = 6.6 Hz, 2H), 3.13 (m, 1H), 2.31
(s, 3H), 1.70-1.45 (m, 4H), 1.16 (d, J = 7.3 Hz, 3H); HRMS
(ESI): m/z 299 (M++ H).
To a stirred solution of Al powder (0.45 g, 16.5 mol) was
added molecular iodine (2.62 g, 11.5 mol) in anhydrous CH2Cl2
(20 mL) at ambient temperature under inert atmosphere. The
reaction mixture was heated under reflux for 1 h. To the resulted
AlI3 solution was cooled to -10 °C. To this cooledAlI3 solution
was added benzyl protected anisole compound (0.1 g, 0.337
mol) slowly and stirring was continued for 0.5 h at -10 °C.
The reaction mixture was quenched with saturated NH4Cl and
sodium thiosulphate. Later the mixture was warmed to ambient
temperature and solvent was removed under reduced pressure.
The residue was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were quenched with sodium thiosulfate
and then washed with water, brine and dried over anhydrous
Na2SO4. Removal of the solvent followed by purification on
column chromatography using silica gel silica gel (60-100
mesh) 40 % EtOAc-hexane as eluent to give product 16 (42
mg, 60 %) as pale yellow syrup; [α]D 27: +4.5 (c = 1.7, MeOH):
IR (neat, cm-1): 3384, 2931, 1611, 1100, 1043, 764, 810; 1H
NMR (300 MHz, CDCl3): δ 6.99 (d, J = 7.6 Hz, 1H), 6.68 (d,
J = 7.6 Hz,1H), 6.60 (s, 1H), 3.80 (s, 3H), 3.57 (t, J = 6.8 Hz,
2H), 3.20-3.07 (m,1H), 2.31 (s, 3H), 1.65-1.41 (m,4H), 1.18
(d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 156.8,
136.3, 132.4, 128.7, 128.3, 121.1, 63.1, 55.4, 33.1, 31.2, 30.8,
21.2, 20.8; HRMS (ESI): Calculated m/z for C13H20O2Na (M+
+ Na) 231.1360, found 231.1365.
Curcuphenol: To a stirred solution of iodoxybenzoic acid
(0.084 g, 0.3 mmol) in DMSO (0.5 mL) was added the
compound 16 (0.042 g, 0.2 mmol), which was dissolved in
dichloromethane (4 mL). The resulting reaction mixture was
stirred at room temperature for a period of 4 h and the completion
of the reaction was confirmed by TLC.After addition of water
(10 mL), the layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with water, brine and dried over anhydrous
Na2SO4. Removal of solvent followed by rapid chromatography
of the resulting residue on silica gel (60-100 mesh) 15 % EtOAc-
hexane as eluent to give product furnished unstable aldehyde.
To a solution of iPrPPh3I (0.192 g, 0.446 mmol, 2.3 equiv)
in THF (3 mL) was added n-BuLi (0.28 mL, 0.42 mmol, 1.5 M
in THF, 2.2 equiv) dropwise at -10 °C. The mixture wasstirred
for 15 min before being cooled to -78 °C.A solution of aldehyde
(0.04 g, 0.194 mmol, 1 equiv) in THF (1 mL) was added
dropwise. After stirring for 1 h, the reaction mixture was
quenched with aqueous saturated NH4Cl and then extracted
with Et2O. The organic layer was washed with brine, dried
with Na2SO4, filtered and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, eluent: 95 %
hexanes 5 % ethyl acetate) to afford methylated curcuphenol
[α]D 23.1 –3.9 (c. 0.26, CHCl3) (Lit) [α]D 25 –5.8 (c. 1.0, CHCl3):
IR (neat, cm-1): 2917, 1612, 1506,1452, 1258; 1H NMR (300
MHz, CDCl3): δ 7.06 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 7.7 Hz,
1H), 6.69 (s, 1H), 5.13 (1H), 3.82 (s, 3H), 3.15(m, 1H), 2.35
(s, 3H), 2.03-1.85 (m, 2H), 1.71-1.62 (m, 1H), 1.69 (br. s,
3H), 1.58-1.49 (m, 1H) 1.56 (br. s, 3H), 1.19(d, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 156.9, 136., 132.8, 131.1,
126.5, 124.9, 121.1, 111.5, 55.3, 37.2, 31.4, 26.3, 25.7, 21.4,
21.1, 17.6. EI-MS: m/z 261 (M++Na).
2-[5-(Benzyloxy)pentan-2-yl]-5-methylphenol (12): To
a well stirred solution of α,β-unsaturated enone 11 (1g, 3.6
mmol) in dioxane (20 mL) was added VOSO4 (0.060g, 0.4
mmol) and tetrabutylammonium bromide (1.9 g, 7.4 mmol)
under inert atmosphere at ambient temperature and then
trifluoro acetate (0.6 mL, 7.2 mmol) was added drop wise
at 0 °C. The reaction mixture was refluxed at 110 °C with
vigorous stirring over a period of 20 h. The reaction mixture
was concentrated under reduced pressure. Then distilled H2O
was added to reaction mixture and then the resultant aqueous
solution of mixture was extracted with Et2O(5 × 20 mL) and
dried over anhydrous Na2SO4.Removal of the solvent followed
by purification on column chromatography using silica gel
(60-100 mesh) 15 % EtOAc-hexane as eluent to give pure
phenolic product (0.204 g, 20 % yield) as colourless oil; IR
1
(neat, cm-1); H NMR (300 MHz, CDCl3): δ 7.34-7.28 (m,
5H), 6.94 (d, J = 7.8 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.55
(s, 1H), 5.74 (bs, 1H), 4.53-4.50 (m, 2H), 3.53-3.43 (m, 2H),
3.07 (m, 1H), 2.25 (s, 3H), 1.70-1.47 (m, 4H), 1.12 (d, J = 6.8
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 152.3, 135.1, 133.8,
128.7, 127.9, 127.8, 126.8, 126.1, 121.4, 116.2, 73.2, 70.8,
35.4, 34.2, 31.2. 27.1, 21.3; ESI-MS: m/z 307 (M++ Na);
HRMS(ESI): Calculated m/z for C19H24O2Na (M+ +Na)
307.1673, found 307.1684
2-[5-(Benzyloxy)pentan-2-yl]-5-methylcyclohexa-2,5-
diene-1,4-dione (13): To a solution of the compound 12 (0.2
g, 0.7 mmol) in methanol was added dropwise a solution of
BTI (0.635 g, 1.477 mmol) in methanol at 0 °C and the resulting
mixture was stirred at 0 °C until TLC showed disappearance
of the compound 13 (2 h). Removal of the solvent followed by
purification on column chromatography using silica gel (60-
100 mesh) 60 % EtOAc-hexane as eluent to give pure pure
quinone compound 0.167 g, 80 %; [α]D 33.8+ 7.7 (c = 0.5,
1
CHCl3). H NMR (300 MHz, CDCl3): δ 7.33-7.21(m, 6H),
6.7(d, J = 2.0 Hz, 1H), 6.47 (s, 1H), 4.44 (s, 2H), 3.43-3.37
(m, 2H), 2.94-2.86 (m, 1H), 2.03 (d, J = 2.0 Hz, 3H), 1.63-
1.54 (m, 2H), 1.54-1.47(m, 2H), 1.12 (d, J = 7.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 183.2, 181.8, 154.0, 138.4, 134.0,
131.2, 128.7, 128.0, 118.2, 73.2, 70.1, 32.4, 31.2, 27.8, 19.8,
15.3; ESI-MS: m/z 321 (M++ Na); HRMS(ESI): Calculated
m/z for C19H22O3Na (M+ +Na) 321.1466, found 321.1451.
To a well stirred solution of p-quinone (0.167 g, 0.56
mmol) in MeOH (18 mL) and H2O (0.5 mL) was added
Na2S2O4 (0.048 g, 0.28 mmol) solid in portions and stirring
was continued for 0.5 h to reduce unstable o-quinone to their
catachol forms. When the reaction was complete, the reaction
mixture was concentrated under reduced pressure. The residue
was extracted with Et2O(3 × 10 mL) and filtered. The combined

Vol. 28, No. 4 (2016)
Total Synthesis of S (+)-Curcuphenol, S (+)-Curcuquinone and S (+)-Curcuhydroquinone 775
organic layers were washed with water, brine and dried with
Na2SO4. Removal of the solvent followed by purification on
column chromatography using silica gel (60-100 mesh) 15 %
Na2SO4. Removal of solvent followed by rapid chromatography
of the resulting residue on silica gel with to furnished unstable
aldehyde.
EtOAc-hexane as eluent to afford desired pure catachol product
To a solution of iPrPPh3I (0.174 g, 0.389 mmol) in THF
(3 mL) was added n-BuLi (0.24 mL, 0.372 mmol, 1.5 M in
THF) dropwise at -10 °C. The mixture was stirred for 15 min
before being cooled to -78 °C. A solution of aldehyde (0.04 g,
0.169 mmol) in THF (1 mL) was added dropwise.After stirring
for 1 h, the reaction mixture was quenched with aqueous
saturated NH4Cl and then extracted with Et2O. The organic
layer was washed with brine, dried with Na2SO4, filtered and
concentrated in vacuo. The residue was purified by solvent
followed by purification on column chromatography using
silica gel (60-100 mesh) 5 % EtOAc-hexane as eluent to afford
desired pure curcuhydroquinone dimethyl ether as a clear,
colourless oil (0.065 g, 65 %); syrup; IR (neat, cm-1): 2961,
32.2
12 (0.138 g) with 82 % yield as colourless syrup oil; [α]D
:
- + 2.7 (c = 0.47, CHCl3): IR (neat, cm-1) 3420, 2922, 1461,
1084, 738, 563; 1H NMR(300 MHz, CDCl3): δ 7.30-7.24 (m,
5H), 6.52-6.48 (d, 2H), (br, 1H), 4.52 (s, 2H), 4.32 (br, 1H),
3.54-3.36 (m, 2H), 3.11-2.98 (m, 1H), 1.92-1.82 (m, 1H), 1.65-
1.47 (m, 3H), 1.19 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3; HRMS (ESI): Calculated m/z for C19H25O3 (M++ H)
301.0000, found 301.0000.
4-(2,5-Dimethoxy-4-methylphenyl)pentan-1-ol (14):
To the stirred solution of catachol derivative (200 mg, 0.67
mmol) in DMSO (5 mL) was added pulverized KOH (150
mg, 2.68 mmol) in portions. Then MeI (0.2 mL, 3.35 mmol)
was added slowly dropwise at 0 °C and stirring was continued
for 12 h. Removal of solvent followed by purification on column
chromatography solvent followed by purification on column
chromatography using silica gel (60-100 mesh) 2 % EtOAc-
hexane as eluent to afford desired pure colourless liquid; IR
(neat, cm-1) 2923, 1630, 1455, 1050, 738, 697; 1H NMR (300
MHz, CDCl3): δ 7.30-7.24 (m, 5H), 6.57(d, 2H), 4.43 (s, 2H),
3.74 (s, 3H), 3.72 (s, 3H), 3.39 (td, J = 6.0, 1.5 Hz, 2H), 3.18-
3.05 (m, 1H), 2.15 (s, 3H), 1.69-1.46 (m, 4H), 1.18 (d, J = 6.8
Hz, 3H); HRMS (ESI): Calculated m/z for C21H28O3Na (M+ +
Na) 351.1936, found 351.1950.
1
1464, 1398, 1206, 1048, 825, 798; H NMR (300 MHz,
CDCl3): δ 6.67(d, 2H), 5.13 (br. t, J = 7.2 Hz, 1H), 3.80 (s,
3H), 3.78 (s, 3H), 3.15 (m, 1H), 2.22 (s, 3H), 2.01-1.85 (m,
2H), 1.68 (s, 3H), 1.67-1.56 (m, 2H), 1.55 (s, 3 H), 1.20 (d, J
= 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 151.8, 150.8,
134.0, 131.1, 124.8, 124.2, 114.3, 109.8, 56.4, 56.1, 37.3, 31.8,
26.3, 25.7, 21.3, 17.6, 16.1); EI-MS: m/z 261 (M++ Na).
Curcuquinone: Solution of CAN (0.324 g, 0.591 mmol)
in H2O (2 mL) was added dropwise to a solution of Curcu-
hydroquinone dimethyl ether (15) (0.050 g, 0.19 mmol) in
MeCN (4 mL) and one drop of petroleum ether at room tempe-
rature. The reaction was stirred for 0.5 h before being extracted
into CH3Cl (2 × 10 mL), concentrated in vacuo and followed
by purification on column chromatography using silica gel
(60-100 mesh) 5 % EtOAc-hexane as eluent to afford desired
pure curcuquinone as a bright yellow oil (0.0185 g, 42 %).All
characterization data matched that reported in the literature;
To a stirred solution of Al powder (500 mg, 18.5 mmol)
was added molecular iodine (3.3 g, 12.9 mmol) in anhydrous
CH2Cl2 (40 mL) at ambient temperature under inert atmos-
phere. The reaction mixture was heated under reflux for 1 h.
To the resultedAlI3 solution was cooled to -10 °C. To this cooled
AlI3 solution was added benzyl protected compound (120 mg,
0.37 mmol) dropwise and stirring was continued for 0.5 h at
-10 °C. The reaction mixture was quenched with saturated
NH4Cl. Later the mixture was warmed to ambient temperature
and solvent was removed under reduced pressure. The residue
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with sodium thiosulfate followed by
washed with water, brine and dried with Na2SO4. Removal of
the solvent followed by column chromatography using silica
gel (60-100 mesh) 30 % EtOAc-hexane as eluent to afford
desired pure furnished required benzyl deprotected alcohol
product (53 mg, 60 %) as pale yellow liquid. IR (neat, cm-1):
1
IR (neat, cm-1): 2961, 1464, 1398, 1206, 1048, 825, 798; H
NMR (300 MHz, CDCl3): δ 6.69 (s, 1H), 6.68 (s, 1H), 5.13
(br. t, J = 7.2 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.15 (m, 1H),
2.22 (s, 3H), 2.01-1.85 (m, 2H), 1.68 (s, 3H), 1.67-1.56 (m,
2H), 1.55 (s, 3 H), 1.20 (d, J = 7.0 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 151.8, 150.8, 134.0, 131.1 (C-6), 124.8, 124.2,
114.3, 109.8, 56.4, 56.1, 37.3, 31.8, 26.3, 25.7, 21.3, 17.6,
16.1, EI-MS: m/z 255 (M++Na).
Curcuhydroquinone: To a well stirred solution of curcu-
quinone (2) (0.03 g, 0.129mmol) in MeOH (6 mL) and H2O
(0.1 mL) was added Na2S2O4 (0.044 g, 0.258 mmol) solid in
portions and stirring was continued for 0.5 h. When the reaction
was completed, the reaction mixture was concentrated under
reduced pressure. The residue was extracted with Et2O(3 × 10
mL) and filtered. The combined organic layers were washed
with water, brine and dried with Na2SO4. Removal of the
solvent followed by purification on column chromatography
using silica gel (60-100 mesh) 10 % EtOAc-hexane as eluent
to afford desired pure to afford desired pure product 1 0.024 g
with 80 % yield as colourless syrup, [α] D 20 + 47.0 (c 1.0,
CH3Cl) Lit. (S)-enantiomer [α] D 20 + 47.1 (c 1.0, CH3Cl); 1H
NMR (CDCl3, 300 MHz) 6.59 (s, 1H), 6.57 (q, 1H), 5.13 (m,
1H, 5-H), 4.32 (br. s, 1H, OH), 4.28 (br. s, 1H, OH), 2.94 (m,
1H), 2.18 (s, 3H,), 2.00-1.89 (m, 2H, 4-H2), 1.69 (q, 3H), 1.67-
1.54 (m, 2H), 1.55 (d, 3H), 1.21 (d, 3H) 13C NMR (CDCl3, 75
MHz) 147.8, 146.6, 132.2, 131.7, 124.5, 121.7, 117.9, 113.4,
1
3363, 2937, 1505, 1464, 1398, 1209, 1046; H NMR (400
MHz, CDCl3): δ 1.21 (d, J = 6.8 Hz, 3H), 1.44 (s, 1H, OH,
D2O exchangeable), 1.44-1.65 (m, 2H), 2.20 (s, 3H), 3.17
(sext., J = 6.8 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H),
3.79 (s, 3H), 6.67 (d, 2H); EI-MS: m/z 261 (M++Na).
1,4-Dimethoxy-2-methyl-5-(6-methylhept-5-en-2-
yl)benzene (15): To a stirred solution of iodoxybenzoic acid
(0.070 g, 0.251 mmol) in DMSO (0.5 mL) was added the
compound 14 (0.04 g, 0.167 mmol), which was dissolved in
DCM (4 mL). The resulting reaction mixture was stirred at
room temperature for a period of 4 h and the completion of
the reaction was confirmed by TLC. After addition of water
(10 mL), the layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were washed with water, brine and dried over anhydrous

776 Chinta et al.
Asian J. Chem.
37.4, 31.4, 26.0, 25.7,21.1, 15.4, 12.7. EI-MS: m/z 257 (M+ +
Na).
give an imide 6 [7,8]and to this added NaHMDS followed by
addition of MeI at -78 °C gave the chiral compound 7 in 76 %
yield with high diastereoselectivity (> 99 %). The resultant
Evans product was then reduced by NaBH4 in MeOH to furnish
the enantiomerically pure alcohol in 70 % yield.
RESULTS AND DISCUSSION
In retro synthetic analysis, outlined in Scheme-I, we envi-
saged that the target molecules prepared from o-valerolactone
4 takes the advantage of Evans asymmetric methylation of
5-(benzyloxy)pentanoic acid 5 to correctly install the chiral
methyl centre at C-2 position, an oxidative aromatization using
iodine in methanol. Then a regioselective oxidation of the
phenol derivative to derive o-quinone would easily provide
the final target molecules.
Oxidation of chiral alcohol under Swern conditions gave
the aldehyde in quantitative yield, which was immediately
subjected to C1-wittig olefination with triphenylphosphonium
iodide using n-butyl lithium at 0 °C to afford the olefin 8 in 84
% yield. The olefin derivative 8 was then converted into the
corresponding primary alcohol by hydroboration with 9-BBN
dimer in dry THF followed by oxidation with H2O2 in the
presence of sodium hydroxide with 70 % yield [9]. Swern
oxidation of the resulting primary alcohol intermediate gave
the desired aldehyde 9 in quantitative yield, which was treated
with buten-3-one in presence of diethylamine trimethylsilane
under refluxing CH3CN for longer hours gave the Michael
adduct in 75 % yield. Then after, the treatment of Michael adduct
with a solution of 5 % aqeous KOH with tetrabutylammonium-
hydroxide in diethylether/THF under reflux conditions gave
the desired Robinson annulated enone 10 in 80 % yield as a
diastereomeric mixture. Later on, the racemic enone 10 was
treated with CH3MgI to afford the tert-alcohol in 72 % yield.
When the resultant tert-alcohol treated with pyridinium
chlorochromate promotes [1,3]-oxidative rearrangement to
produce α,β-unsaturated cyclo-hexenone 11 (Scheme-II) in
70 % yield [10]. Here the key intermediate enone 11 was trans-
formed into methyl phenyl ether via oxidative aromatization
under drastic reflux condition of molecular iodine and
methanol mixture with 66 % yield [11], which was subjected
to selective debenzylation with AlI3 at -10 °C under inert
atmosphere provides primary alcohol 16 in 60 % yield without
disturbing the methyl ether protection [12], which was oxidized
into aldehyde using IBX in DMSO/DCM provided 84 % yield
and sequential elaboration made with the respective Wittig
olefination reagent using n-butyl lithium in 65 % yield.
Afterward the resultant curcuphenol methyl ether was
treated with AlI3 at 0 °C under acid mediated demethylation
condition accomplished natural bioactive (-)-curcuphenol in
64 % yield [13] (Scheme-III). On the other hand, oxidative
Ph
O
H
O
O
O
N
O
O
OBn
11
BnO
O
4
7
OH
O H
O
OH
2
1
3
Scheme-I: Retro synthetic analysis of target molecules (-)-curcuphenol
(1), (-)-curcuquinone (2) and (-)-curcuhydroquinone (3)
Accordingly, the synthesis of the target molecules started
from the commercially available o-valerolactone (Scheme-II)
which was on treatment with BnCl with KOH under refluxed
toluene for 16 h provides acid derivative of benzylether [4,6].
Then we synthesized (R or S) oxazolidinone from D-phenyl-
alanine, a chiral auxiliary used to fixed stereo centre of the
methyl substituent at benzylic position in 7. For this first the
acid derivative 5 was coupled with lithiated chiral auxiliary
generated by consecutive addition of triethylamine, pivoloyl
chloride and lithium chloride at -20 °C in anhydrous THF to
Ph
N
Ph
N
O
O
O
O
O
a
d, e,f
b
c
BnO
BnO
BnO
g, h
OH
O
O
O
O
7
4
5
6
O
BnO
BnO
i, j
k, l
BnO
BnO
O
O
9
8
10
11
Scheme-II: a. BnCl, KOH, PhMe, reflux, 16 h; (b) (i) PivCl, NEt3, THF, -20 °C, then, LiCl, 84 %; (c) NaHMDS, THF, MeI, HMPA, -78 °C to -30 °C,
2 h, 76 %; (d) NaBH4, MeOH, 0 °C to room temperature, 2 h, 70 %; (e) (COCl)2, DMSO, CH2Cl2, -78 °C, then, Et3N, room temperature,
2 h, quantitative yield; (f) n-BuLi, Ph3PCH2I, THF, 0 °C to room temperature, 3 h, 84 %; (g) 9-BBN-H, THF, room temperature, 2 h, then
20 % NaOH, 30 % H2O2, room temperature, 12 h, 70 %; (h) (COCl)2, DMSO, CH2Cl2, -78 °C, then Et3N, room temperature, 2 h,
quantitative yield; (i) MVK, TMSNEt2, CH3CN, room temperature to reflux, 48 h, 75 %; (j) Bu4NOH, THF/ether/5 % KOH, reflux, 8 h,
80 %; (k) Mg, CH3I, ether, 0 °C to room temperature, 72 %; (l) PCC, CH2Cl2, 0 °C to room temperature, 2.5 h, 70 %

Vol. 28, No. 4 (2016)
Total Synthesis of S (+)-Curcuphenol, S (+)-Curcuquinone and S (+)-Curcuhydroquinone 777
OMe
OH
OH
MeO
O
h, i
a
c, d
b
OH
OH
14
OH
BnO
12
OBn
13
OMe
OBn
OH
16
11
j, k, l
e
OH
O
OMe
g
f
OH
OMe
O
1
3
2
15
Scheme-III:(a) VOSO4, Bu4NBr, O2, 1,4-dioxane, room temperature to reflux, 48 h; 45 % (b) i) BTI, MeOH, room temperature 3 h, 80 %; ii)
Na2S2O4, 30 min, room temperature, 84 %; (c) CH3I, KOH, 0 °C to room temperature,12 h, 60 %; (d) AlI3, CH2Cl2, -10 °C, 30 min, 70
%; (e) (i) IBX, DMSO:CH2Cl2 (1:9), room temperature, 4h, 82 %; (ii) Ph3P=CH(CH3)2I, n-BuLi, THF, -78 °C, 3 h, 52 %; (f) CAN,
CH3CN/H2O, room temperature, 56 %; (g) Na2S2O4, THF, H2O, room temperature, 78 %; (i) I2, MeOH, room temperature to reflux,12 h,
66 %; (h) AlI3, CH2Cl2, -10 °C, 30 min, 60 %; (j) IBX, DMSO:CH2Cl2 (1:9), room temperature, 4 h, 84 %; (k) Ph3P=CH(CH3)2I, n-BuLi,
THF, -78 °C, 3 h, 65 %; (l) AlI3, CH2Cl2, 0 °C, 1 h, 64 %
aromatization of a key intermediate 11 usingVOSO4, Bu4NBr
and TFA under atmospheric oxygen in refluxing 1,4-dioxane
provided the corresponding phenol derivative 12 in 45 %
isolated yield [14]. Then oxidation of 12 with bis(trifluoro-
acetate)iodobenzene (BTI) in methanol gave the p-quinone in
80 % yield [15], which undergoes reductive aromatization with
sodium dithionate delivered compound 13 in 84 % yield. Here
after methylation of 13 with MeI in the presence of KOH in
DMSO gave the dimethyl ether compound [16] followed by
debenzylation usingAlI3 at -10 °C under inert atmosphere gave
the primary alcohol 14 in 70 % yield.
lation, [1,3]-oxidative rearrangement, oxidative aromatization,
regioselective oxidation of phenol to p-quinone as key steps.
Our synthetic sequence is useful for an easy access of aromatic
bisabolenes such as heliannuols and glandulone of biological
importance.
ACKNOWLEDGEMENTS
One of the authors (RMK) thanks to Director, Evolva
Biotech for the providing grant for research.
REFERENCES
Oxidation of the alcohol 15 with IBX in DMSO/DCM
gave the aldehyde in 82 % yield, which was then subjected
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presence of n-butyllithium gave the dimethoxyaromatic
bisabolene 15 in 52 % yield [14].Finally, oxidative demethylation
of dimethoxybisabolene 15 using cericammonium nitrate gave
the natural (-)-curcuquinone in 56 % yield [18]. The natural
(-)-curcuquinone was subjected to reductive aromatization
using sodium dithionate gave the (-)-curcuhydroquinone in
78 % yield [17] (Scheme-III).
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Conclusion
In conclusion, we have demonstrated the synthesis of
phenolic center of aromatic bisabolene skeleton done by two
complementary methods involving oxidative aromatization
using iodine in methanol and vanadium catalyst induced
aromatization. The side chain of bisabolene skeleton 1 and 2
was elaborated using respectiveWittig olefination. The natural
products (+)-curcuphenol, (-)-curcuhydroquinone and (+)-
curcuquinone have been prepared from o-valerolactone
employing Evan’s asymmetric methylation, Robinson annu-

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