Structure revision of HM-3, an aromatic sesquiterpene isolated from the phytopathogenic fungus Helicobasidium mompa. First total syntheses of HM-3 and HM-4

Article abstract of DOI:10.1016/j.tet.2006.07.062

The first total syntheses of HM-3 and HM-4, aromatic sesquiterpenes isolated from the phytopathogenic fungus Helicobasidium mompa, have been accomplished. The structure assigned to the sesquiterpene HM-3 was found to be incorrect by total synthesis. A Cla

Full text of DOI:10.1016/j.tet.2006.07.062

Tetrahedron 62 (2006) 9393–9402
Structure revision of HM-3, an aromatic sesquiterpene isolated
from the phytopathogenic fungus Helicobasidium mompa.
First total syntheses of HM-3 and HM-4
*
A. Srikrishna and P. C. Ravikumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
Received 24 April 2006; revised 2 July 2006; accepted 20 July 2006
Available online 10 August 2006
Abstract—The first total syntheses of HM-3 and HM-4, aromatic sesquiterpenes isolated from the phytopathogenic fungus Helicobasidium
mompa, have been accomplished. The structure assigned to the sesquiterpene HM-3 was found to be incorrect by total synthesis. A Claisen
rearrangement–RCM reaction based strategy was employed for the total synthesis of the aromatic sesquiterpene HM-4 (cuparene-1,2-diol),
which on selective monoacetylation established the structure of HM-3, a cuparene derivative.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
structure of HM-2 as cuparene-1,4-diol monoacetate 5.5
In continuation, herein, we describe our studies on the syn-
thesis6 of the compound having structure 3 and cuparene-
1,2-diol 4, and revision of the structure for HM-3 as a
cuparenoid.
The phytopathogenic fungus Helicobasidium mompa Tanaka
is responsible for the violet root rot against mulberry and
several other fruit trees. In the course of a study on the mech-
anism of violet root rot, Nohara and co-workers have inves-
tigated the fungus, and reported the isolation and structure
elucidation of four aromatic sesquiterpenes from the metha-
nolic extract of the mycelium grown with H. mompa, which
was obtained from infected mulberry roots.1 Based on
preliminary observations, it was speculated that all the com-
pounds possessed anti-oxidant as well as antibiotic activities
similar to those of the higher oxygenated cuparene ana-
logues, lagopodins and helicobasidins.2 Of the four sesqui-
terpenes, two, HM-1 (1) and HM-4 (4), were found to
belong to the cuparene class, whereas the structures of the
remaining two, HM-2 (2) and HM-3 (3), were assigned as
herbertanes on the basis of the 1D and 2D NMR spectros-
copy. Incidentally, isolation of HM-4 (4) (same as cuparene-
1,2-diol) has been reported earlier in 1982 from the liverwort
Raduia perrottetii and subsequently from the liverwort
Herbertus aduncus, and from the Japanese liverworts Lejeu-
nea aquatica and Lejeunea japonica.3 Since herbertanes are
considered as chemical markers of the liverworts belonging
to the genus Herbertus,4 and Helicobasidium is known to
contain helicobasidins,2 which are higher oxygenated deriv-
atives of cuparenes, we have undertaken the synthesis of
HM-1 to 4 1–4. Recently, we carried out the total synthesis
of putative structure 2 of HM-2, as well as cuparene-1,4-
diol and its methyl and acetyl derivatives and revised the
HO
AcO
AcO
OH
OH
4 (HM-4)
HO
OH
3 (HM-3)
MeO
1 (HM-1)
2 (HM-2)
HO
AcO
5 (HM-2 REVISED)
cuparene
herbertene
2. Results and discussion
For the synthesis of the putative structure 3 of HM-3, an
orthoester Claisen rearrangement7 and a ring-closing meta-
thesis reaction (RCM)8 based strategy were employed
(Scheme 1) starting from 2,6-dimethoxy-3-methylaceto-
phenone 6. The acetophenone9 6 was prepared from 4-methyl-
resorcinol dimethyl ether 7 in three steps (formylation,
Grignard reaction, and oxidation). Since the Wittig or
Horner–Wadsworth–Emmons reactions were unsuccessful,
probably due to the steric crowding of the ketone group,
a three-step protocol was used for the efficient conversion
of the acetophenone 6 into the cinnamyl alcohol 8a, the pre-
cursor for the Claisen rearrangement. Thus, Grignard reac-
tion of the acetophenone 6 with vinylmagnesium bromide
* Corresponding author. Tel. +91 80 22932215; fax: +91 80 23600529;
e-mail: ask@orgchem.iisc.ernet.in
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.062

9394
A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
OMe
OMe
OMe
OMe
O
OH
R
a
b
c
76%
OMe
95%
84%
OMe
OMe
OMe
10 R=CHO
d, 100%
7
6
9
8a R=CH2OH
e, 87%
OMe
OMe
OMe
OMe
f
h
84%
R
100%
COOEt
OH
OMe
12a
OMe
13a R=CH2OH
14a R=CHO
11a
g, 89%
i, 100%
OMe
OMe
OMe
j
93%
k
73%
OH
O
O
OMe
15a
OMe
17a
OMe
16a
l, 100%
OMe
OMe
OMe
OMe
m
99%
o
75%
OR
88%
O
OMe
OMe
19 R=H
20 R=CSSMe
21a
18a
p, 64%
OH
OAc
q
71%
OH
OH
3
22
Scheme 1. Reagents and conditions: (a) (i) n-BuLi, TMEDA, DMF, THF, 0 ꢀC/rt, 4 h; (ii) MeMgI, Et2O, 0 ꢀC, 30 min; (iii) PCC, silica gel, CH2Cl2, 8 h;
(b) CH2]CHMgBr, THF, 0 ꢀC/rt, 4 h; (c) PCC, silica gel, CH2Cl2, 8 h; (d) LAH, Et2O, À50 ꢀC, 45 min; (e) CH3C(OEt)3, EtCO2H (catalytic), 180 ꢀC,
48 h; (f) LAH, Et2O, 0 ꢀC, 30 min; (g) PCC, silica gel CH2Cl2, 15 min; (h) CH2]CHMgBr, THF, À20 ꢀC, 10 min; (i) PhCH]RuCl2(PCy3)2 (5 mol %),
CH2Cl2, 3 h; (j) PCC, silica gel, CH2Cl2, 1 h; (k) NaH, CH3I, THF, DMF, rt, 12 h; (l) H2 (1 atm), 10% Pd–C, EtOH, 1 h; (m) NaBH4, MeOH, 0 ꢀC, 5 min;
(n) NaH, THF, imidazole (catalytic), CS2, CH3I, reflux, 4.5 h; (o) n-Bu3SnH, AIBN, C6H6, reflux, 3 h; (p) MeMgI, p-cymene, reflux, 8 h; (q) Ac2O, py,
DMAP, CH2Cl2, rt, 2 h.
furnished the tertiary allyl alcohol 9 in 95% yield. Oxidation
of the alcohol 9 with pyridinium chlorochromate (PCC) and
silica gel in methylene chloride led to the 1,3-transposition10
to generate the cinnamaldehyde 10, which on reduction with
lithium aluminum hydride (LAH) in ether generated the
cinnamyl alcohol 8a in 84% yield (two steps). Johnson’s
orthoester variant of the Claisen rearrangement was em-
ployed for the generation of the g,d-unsaturated ester con-
taining the first quaternary carbon atom. Thermal activation
of the cinnamyl alcohol 8a with triethyl orthoacetate and
a catalytic amount of propionic acid in a sealed tube fur-
nished the pentenoate 11ain 87% yield. A three-step protocol
was employed for the conversionof the ester 11a into the hep-
tadienol 12a, the precursor for the RCM reaction. Thus, re-
duction of the ester 11a with LAH followed by oxidation of
the resultant primary alcohol 13a with PCC and silica gel in
methylene chloride furnished the aldehyde 14a. Grignard
reaction of the aldehyde 14a with vinylmagnesium bromide
generated the heptadienol 12a. RCM reaction of the dienol
12a in methylene chloride with 5 mol % of Grubbs’ first
generation catalyst [PhCH]RuCl2(PCy3)2] generated the
cyclopentenol 15a in quantitative yield, which on oxidation
with PCC and silica gel in methylene chloride furnished
the cyclopentenone 16a. One-step dimethylation of the
cyclopentenone 16a with sodium hydride and methyl iodide
in THF and DMF created the second quaternary carbon atom
vicinal to the first one to furnish the cyclopentenone 17a
containing the complete carbon framework of herbertanes.
Hydrogenation with 10% palladium over carbon as the
catalyst quantitatively transformed the enone 17a into cyclo-
pentanone 18a. Barton’s radical deoxygenation protocol11,12
was employed for the reductive deoxygenation of the ketone
18a. Reduction of the ketone 18a with sodium borohydride
generated an epimeric mixture of the alcohol 19 in quantita-
tive yield. Treatment of the alcohol 19 with sodium hydride
and imidazole in THF followed by reaction of the resultant
alkoxide with carbon disulfide and methyl iodide generated
the dithiocarbonate 20. Reaction of the dithiocarbonate
20 with tri-n-butyltin hydride and a catalytic amount of
azobisisobutyronitrile (AIBN) in refluxing benzene fur-
nished herbertene-1,5-diol dimethyl ether 21a. Boron tribro-
mide or other acidic reagents mediated cleavage of the
methyl ether in 21a, however, failed to generate the herber-
tenediol 22, and produced only the cleaved product,

A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
9395
4-methylresorcinol. Hence, demethylation was carried out
using a Grignard reagent. Thus, refluxing a p-cymene solu-
tion of the dimethyl ether 21a with methylmagnesium iodide
furnished herbertene-1,5-diol 22. Regioselective acetylation
of the less hindered alcohol in the diol 22 with pyridine and
acetic anhydride in methylene chloride for 2 h furnished
the monoacetate 3 in 71% yield. The 1H NMR spectrum of
the monoacetate 3, however, was found to be different13
from that reported1 for HM-3, which clearly established
that the proposed structure needs to be revised.
catalyst generated the cyclopentenol 15b, which on PCC
oxidation furnished the enone 16b. One-pot dimethylation
of the enone 16b followed by catalytic hydrogenation of the
resultant enone 17b furnished 1,2-dimethoxy-a-cuparenone
18b. Treatment of the ketone 18b with 1,2-ethanedithiol in
the presence of a catalytic amount of iodine15 generated the
thioketal 27, which on desulfurization with Raney nickel fur-
nished cuparene-1,2-diol dimethyl ether 21b in 80% yield
(two steps). Cleavage of the methyl ethers in 21b with boron
tribromide furnished cuparene-1,2-diol 4, which exhibited
1H NMR spectrum identical to that reported1,3 for HM-4.
Regioselective acetylation of the less hindered alcohol in
the diol 4 with acetic anhydride and pyridine in methylene
chloride furnished the monoacetate 28. The 1H NMR spectral
data of the monoacetate 28 was found to be identical to that
reported1 for HM-3, which established the structure of the
natural product HM-3 as a cuparene derivative 28.16
It was reasoned, like HM-1 (1), HM-2 (5),5 and HM-4 (4),
that HM-3 might also be a derivative of cuparene, and an
acetate analog of HM-4 (cuparene-1,2-diol 4) was consid-
ered as a possibility, since the NMR spectrum of the natural
HM-3 clearly indicated that it contains two ortho coupled
aromatic protons. To test the validity of this hypothesis
and also to confirm the structure of HM-4,6 the synthesis
of cuparene-1,2-diol 4 was undertaken, Scheme 2.
In conclusion, we have accomplished an efficient total syn-
thesis (in 16 steps from the acetophenone 6 with an average
yield of 88% for each step) of the putative structure 3 of
HM-3 and proved that the structure needs revision. We rea-
soned it to be a cuparene derivative. To substantiate further,
the first total synthesis of cuparene-1,2-diol (HM-4) 4 was
accomplished (in 13 steps from the coumarin 24 with an
average yield of 90% for each step). Selective monoacetyla-
tion of cuparene-1,2-diol 4 established the structure of HM-3
as 28. A combination of a Claisen rearrangement, a RCM
reaction and an alkylation was strategically employed for
the efficient construction of cyclopentanes containing two
vicinal quaternary carbon atoms.
The cinnamyl alcohol 8b was identified as a suitable starting
material, which was prepared starting from 3-methylcatechol
diacetate 23 via the coumarin 24 as reported in the litera-
ture.14 Thus, Pechmann reaction of the diacetate 23 with
ethyl acetoacetate and 80% sulfuric acid generated the cou-
marin 25, which on etherification with potassium carbonate
and methyl iodide furnished the coumarin 24. Reduction of
the coumarin 24 with LAH in THF at À50 ꢀC followed by
regioselective etherification of the phenolic hydroxy group
in the resultant diol 26 with potassium carbonate and methyl
iodide in refluxing acetone furnished the cinnamyl alcohol 8b
in 81% yield. The orthoester Claisen rearrangement of the
cinnamyl alcohol 8b with triethyl orthoacetate and propionic
acid generated the pentenoate 11b, which was converted into
the aldehyde 14b via the alcohol 13b. Grignard reaction of
the aldehyde 14b with vinylmagnesium bromide followed
by RCM reaction of the resultant dienol 12b with Grubbs’
3. Experimental
Melting points were recorded using Mettler FP1 melting
point apparatus in capillary tubes and are uncorrected. IR
a,b
c,d
O
O
OR OH
AcO
OAc
OR
MeO
23
26. R = H
25. R = H
8b. R = Me
24. R = Me
e-g
O
i-k
h
R
R
R
OMe
OH
MeO
OMe
MeO
MeO
OMe
12b
11b. R = COOEt
13b. R = CH2OH
14b. R = CHO
16b. R = H
17b. R = Me
l,m
p
n,o
X
MeO
OMe
RO
OR
AcO
OH
18b. X = O
27. X = SCH2CH2S
21b. R = Me
4. R = H
28
Scheme 2. Reagents and conditions: (a) CH3COCH2COOEt, 80% aq H2SO4, 80 ꢀC, 45 min; (b) K2CO3, Me2CO, MeI, reflux, 5 h; (c) LAH, THF, À50 ꢀC,
30 min, 92%; (d) K2CO3, MeI, Me2CO, reflux, 5 h, 88%; (e) CH3C(OEt)3, EtCO2H, sealed tube, 180 ꢀC, 36 h, 80%; (f) LAH, THF, 0 ꢀC, 30 min, 95%;
(g) PCC, silica gel CH2Cl2, rt, 15 min, 84%; (h) CH2]CHMgBr, THF, À20 ꢀC, 10 min, 77%; (i) PhCH]RuCl2(PCy3)2 (5 mol %), CH2Cl2, 3 h, 100%; (j)
PCC, silica gel, CH2Cl2, 1 h, 96%; (k) NaH, CH3I, THF, DMF, rt, 12 h, 98%; (l) H2 (1 atm), 10% Pd–C, EtOH, 1 h, 100%; (m) (CH2SH)2, I2, 0 ꢀC/rt,
12 h, 93%; (n) Raney Ni, EtOH, reflux, 3 h, 100%; (o) BBr3, CH2Cl2, À40 ꢀC, 4 h, 62%; (p) Ac2O, py, CH2Cl2, rt, 3 h, 68%.

9396
A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
spectra were recorded on Jasco FTIR 410 spectrophotometer.
1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded on JNM l-300 spectrometer. Unless otherwise
specified a 1:1 mixture of CDCl3 and CCl4 was used as sol-
vent for preparing the NMR samples. The chemical shifts
(d ppm) and coupling constants (Hz) are reported in the
standard fashion with reference to either internal tetra-
methylsilane (for 1H) or the central line (77.0 ppm) of
CDCl3 (for 13C). In the 13C NMR spectra, the nature of the
carbons (C, CH, CH2 or CH3) was determined by recording
the DEPT-135 spectra, and is given in parentheses. High-res-
olution mass spectra were recorded using Micromass Q-TOF
micromass spectrometer using electrospray ionization.
obtained above in CH2Cl2 (4 mL) and vigorously stirred
for 8 h at rt. The reaction mixture was then filtered through
a small silica gel column with excess CH2Cl2. Evaporation
of the solvent and purification of the residue on a silica gel
column using ethyl acetate–hexane (1:10) as eluent fur-
nished the acetophenone 6 (970 mg, 85%) as oil.9b,c IR
(Neat): nmax/cmÀ1 1706, 1600; 1H NMR (300 MHz,
CDCl3+CCl4): d 7.07 and 6.56 (2H, 2Âd, J 8.4 Hz), 3.78
(3H, s), 3.70 (3H, s), 2.46 (3H, s), 2.21 (3H, s); 13C NMR
(75 MHz, CDCl3+CCl4): d 202.0 (C), 155.2 (C), 154.7 (C),
131.7 (CH), 126.1 (C), 123.4 (C), 106.6 (CH), 62.0 (CH3),
55.7 (CH3), 32.3 (CH3), 15.2 (CH3); HRMS: m/z calcd for
C11H14O3Na (M+Na): 217.0841, found: 217.0846.
3.1. 2,6-Dimethoxy-3-methylbenzaldehyde
3.3. 2-(2,6-Dimethoxy-3-methylphenyl)but-3-en-2-ol (9)
To a cold (0 ꢀC) magnetically stirred solution of 4-methyl-
resorcinol dimethyl ether 7 (1.11 g, 7.24 mmol) and
N,N,N,N-tetramethylethylenediamine (1.14 mL, 7.6 mmol)
in anhydrous THF (5 mL) was added drop wise a solution
of n-BuLi (2.5 M in hexane, 3.48 mL, 8.69 mmol) over a
period of 10 min and stirred at rt for 1 h. It was cooled to
0 ꢀC and DMF (0.85 mL, 10.9 mmol) was added drop wise
and stirred at rt for 4 h. It was slowly poured onto cold
saturated aq NH4Cl (20 mL) and extracted with ether
(2Â10 mL). The combined organic layer was washed with
3 N aq HCl (20 mL) and brine, and dried (Na2SO4). Evapo-
ration of the solvent and purification of the residue on a silica
gel column using ethyl acetate–hexane (1:10) as eluent
furnished 2,6-dimethoxy-3-methylbenzaldehyde9a (1.21 g,
92%) as a solid. Mp: 87–88 ꢀC; IR (Neat): nmax/cmÀ1
2767, 1690, 1597, 1581; 1H NMR (300 MHz, CDCl3+CCl4):
d 10.41 (1H, s), 7.28 and 6.63 (2H, 2Âd, J 9.0 Hz), 3.87 (3H,
s), 3.80 (3H, s), 2.21 (3H, s); 13C NMR (75 MHz,
CDCl3+CCl4): d 188.7 (CH), 160.4 (C), 160.3 (C), 136.8
(CH), 123.9 (C), 118.8 (C), 106.7 (CH), 61.9 (CH3), 55.8
(CH3), 15.0 (CH3).
To a cold (À20 ꢀC) magnetically stirred solution of the
ketone 6 (520 mg, 2.68 mmol) in THF (3 mL) was added
a solution of vinylmagnesium bromide [prepared from
Mg (129 mg, 5.36 mmol) and vinyl bromide (0.57 mL,
8.04 mmol) in THF (8 mL)] and stirred at À20 ꢀC for
30 min. The reaction was then quenched with cold saturated
aq NH4Cl solution and extracted with ether (2Â10 mL). The
organic layer was washed with water and brine, and dried
(Na2SO4). Evaporation of the solvent and purification of
the residue on a silica gel column using ethyl acetate–hexane
(1:20) as eluent furnished the tertiary alcohol 9 (567 mg,
1
95%) as oil. IR (Neat): nmax/cmÀ1 3454, 1597; H NMR
(300 MHz, CDCl3+CCl4): d 6.96 and 6.57 (2H, 2Âd,
J 8.4 Hz), 6.27 (1H, dd, J 17.1 and 10.2 Hz), 5.81 (1H, s),
5.16 (1H, dd, J 17.1 and 1.5 Hz), 4.91 (1H, dd, J 10.2 and
1.5 Hz), 3.78 (3H, s), 3.65 (3H, s), 2.19 (3H, s), 1.68 (3H,
s); 13C NMR (75 MHz, CDCl3+CCl4): d 156.8 (C), 156.2
(C), 146.0 (CH), 129.8 (CH), 127.4 (C), 124.4 (C), 109.9
(CH2), 108.2 (CH), 75.9 (C), 61.0 (CH3), 55.8 (CH3), 29.5
(CH3), 16.1 (CH3); HRMS: m/z calcd for C13H18O3Na
(M+Na): 245.1154, found: 245.1166.
3.2. 2,6-Dimethoxy-3-methylacetophenone (6)
3.4. E-3-(2,6-Dimethoxy-3-methylphenyl)but-2-enal (10)
Toafreshlypreparedmagneticallystirredcold(À20 ꢀC)solu-
tion of MeMgI [prepared from Mg (297 mg, 12.22 mmol)
and MeI (1.14 mL, 18.33 mmol) in dry ether (5 mL)] was
added a solution of 2,6-dimethoxy-3-methylbenzaldehyde
(1.1 g, 6.11 mmol) in dry ether (3 mL) over a period of
10 min and stirred at rt for 30 min. The reaction mixture
was poured into ice cold aq NH4Cl solution and extracted
with ether (3Â10 mL). The ether extract was washed with
brine and dried (Na2SO4). Evaporation of the solvent
furnished 1-(2,6-dimethoxy-3-methylphenyl)ethanol (1.15 g,
To a magnetically stirred suspension of PCC (1.36 g,
6.3 mmol) and silica gel (1.35 g) in CH2Cl2 (5 mL) was
added a solution of the alcohol 9 (560 mg, 2.52 mmol) in
CH2Cl2 (4 mL) and vigorously stirred for 8 h at rt. The reac-
tion mixture was then filtered through a small silica gel col-
umn with excess CH2Cl2. Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl
acetate–hexane (1:20) as eluent furnished the aldehyde 10
(466 mg, 84%) as oil. IR (Neat): nmax/cmÀ1 2752, 1672,
1
1635, 1598; H NMR (300 MHz, CDCl3+CCl4): d 10.15
1
97%) as oil. IR (Neat): nmax/cmÀ1 3566, 1603; H NMR
(1H, d, J 8.1 Hz), 7.01 and 6.54 (2H, 2Âd, J 8.4 Hz), 5.93
(1H, d, J 8.1 Hz), 3.73 (3H, s), 3.63 (3H, s), 2.42 (3H, s),
2.20 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4): d 190.2
(CH), 155.6 (C), 155.1 (C), 154.7 (C), 131.5 (CH), 130.8
(CH), 125.8 (C), 123.4 (C), 106.6 (CH), 60.9 (CH3), 55.7
(CH3), 18.9 (CH3), 15.7 (CH3); HRMS: m/z calcd for
C13H16O3Na (M+Na): 243.0997, found: 243.1008.
(300 MHz, CDCl3+CCl4): d 6.97 and 6.57 (2H, 2Âd,
J 8.4 Hz), 5.15 (1H, dq, J 11.4 and 6.6 Hz), 3.84 (3H, s),
3.74 (3H, s), 3.66 (1H, d, J 11.4 Hz), 2.21 (3H, s), 1.52
(3H, d, J 6.6 Hz); 13C NMR (75 MHz, CDCl3+CCl4):
d 156.4 (C), 156.0 (C), 129.6 (CH), 126.1 (C), 123.5 (C),
106.8 (CH), 64.8 (CH), 60.9 (CH3), 55.4 (CH3), 24.4
(CH3), 15.8 (CH3); HRMS: m/z calcd for C11H16O3Na
(M+Na): 219.0997, found: 219.0992.
3.5. E-3-(2,6-Dimethoxy-3-methylphenyl)but-2-en-1-ol
(8a)
To a magnetically stirred suspension of PCC (2.52 g,
11.7 mmol) and silica gel (2.5 g) in CH2Cl2 (8 mL) was
added a solution of the alcohol (1.15 g, 5.87 mmol)
To a cold (À30 ꢀC) magnetically stirred solution of the alde-
hyde 10 (900 mg, 4.1 mmol) in ether (5 mL) was added

A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
9397
LAH (156 mg, 4.1 mmol) in portions. The reaction mixture
was stirred at the same temperature for 30 min and ethyl ace-
tate (2 mL) was added to consume the excess LAH. It was
then quenched with water (5 mL) and extracted with ether
(3Â5 mL). The combined ether extract was washed with
brine and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl
acetate–hexane (2:5) as eluent furnished the alcohol 8a
(896 mg, 100%) as oil. IR (Neat): nmax/cmÀ1 3425, 1598;
1H NMR (300 MHz, CDCl3+CCl4): d 6.98 and 6.55 (2H,
2Âd, J 8.4 Hz), 5.88 (1H, t, J 7.5 Hz), 3.74 (3H, s), 3.69
(2H, dd, J 6.6 and 2.7 Hz), 3.61 (3H, s), 2.30 (1H, br s),
2.20 (3H, s), 2.03 (3H, s); 13C NMR (75 MHz,
CDCl3+CCl4): d 156.0 (C), 155.5 (C), 134.0 (C), 129.9
(CH), 128.2 (CH), 123.5 (C), 123.3 (C), 106.9 (CH), 60.6
(CH2), 60.2 (CH3), 55.8 (CH3), 24.2 (CH3), 15.8 (CH3);
HRMS: m/z calcd for C13H18O3Na (M+Na): 245.1154,
found: 245.1161.
(C), 149.3 (CH), 129.3 (CH), 127.5 (C), 124.4 (C), 107.9
(CH), 104.9 (CH2), 60.6 (CH2), 60.5 (CH3), 55.4 (CH3),
43.5 (C), 43.4 (CH2), 25.9 (CH3), 16.4 (CH3); HRMS: m/z
calcd for C15H22O3Na (M+Na): 273.1467, found: 273.1474.
3.8. 3-(2,6-Dimethoxy-3-methylphenyl)-3-methylpent-
4-enal (14a)
To a magnetically stirred suspension of PCC (555 mg,
2.58 mmol) and silica gel (550 mg) in CH2Cl2 (2 mL) was
added a solution of the alcohol 13a (258 mg, 1.03 mmol)
in CH2Cl2 (2 mL) and stirred at rt for 15 min. The reaction
mixture was then filtered through a small silica gel column
with excess CH2Cl2. Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using ethyl acetate–
hexane (1:20) as eluent furnished the aldehyde 14a (220 mg,
89%) as oil. IR (Neat): nmax/cmÀ1 2737, 1717, 1677, 1597;
1H NMR (300 MHz, CDCl3+CCl4): d 9.52 (1H, t,
J 2.7 Hz), 6.99 and 6.56 (2H, 2Âd, J 8.4 Hz), 6.39 (1H,
dd, J 17.7 and 10.5 Hz), 4.88 (1H, d, J 17.7 Hz), 4.87 (1H,
d, J 10.5 Hz), 3.73 (3H, s), 3.51 (3H, s), 3.01 and 2.80
(2H, 2Âdd, J 16.8 and 2.7 Hz), 2.20 (3H, s), 1.60 (3H, s);
13C NMR (75 MHz, CDCl3+CCl4): d 202.3 (CH), 158.0
(C), 157.0 (C), 148.2 (CH), 130.0 (CH), 126.2 (C), 124.6
(C), 108.0 (CH), 106.9 (CH2), 60.3 (CH3), 55.3 (CH3),
53.9 (CH2), 42.4 (C), 26.3 (CH3), 16.4 (CH3); HRMS:
m/z calcd for C15H20O3Na (M+Na): 271.1310, found:
271.1309.
3.6. Ethyl 3-(2,6-dimethoxy-3-methylphenyl)-3-methyl-
pent-4-enoate (11a)
A solution of the allyl alcohol 8a (130 mg, 0.59 mmol),
triethyl orthoacetate (0.5 mL, 2.93 mmol), and a catalytic
amount of propionic acid (5 mL) was placed in a sealed
tube and heated to 180 ꢀC for 36 h in an oil bath. The reac-
tion mixture was cooled, diluted with ether (5 mL), washed
with 3 N aq HCl (5 mL), saturated aq NaHCO3 solution
(5 mL), and brine, and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column
using ethyl acetate–hexane (1:40) as eluent furnished the
3.9. 5-(2,6-Dimethoxy-3-methylphenyl)-5-methylhepta-
1,6-dien-3-ol (12a)
pentenoate 11a (148 mg, 87%) as oil. IR (Neat): nmax
/
cmÀ1 1734, 1633, 1595; 1H NMR (300 MHz, CDCl3+CCl4):
d 6.94 (1H, d, J 8.4 Hz), 6.55 (1H, dd, J 17.7 and 11.1 Hz),
6.52 (1H, d, J 8.4 Hz), 4.88 (1H, d, J 17.7 Hz), 4.80 (1H, d,
J 11.1 Hz), 3.93 (2H, q, J 6.9 Hz), 3.73 (3H, s), 3.49 (3H, s),
3.12 and 2.85 (2H, 2Âd, J 15.0 Hz), 2.19 (3H, s), 1.58 (3H,
s), 1.07 (3H, t, J 6.9 Hz); 13C NMR (75 MHz, CDCl3+CCl4):
d 171.7 (C), 158.1 (C), 157.4 (C), 148.5 (CH), 129.3 (CH),
127.3 (C), 124.3 (C), 107.8 (CH), 105.7 (CH2), 60.5
(CH3), 59.4 (CH2), 55.5 (CH3), 46.5 (CH2), 43.2 (C), 25.5
(CH3), 14.2 (CH3); HRMS: m/z calcd for C17H24O4Na
(M+Na): 315.1572, found: 315.1551.
To a cold (À20 ꢀC) magnetically stirred solution of the alde-
hyde 14a (160 mg, 0.645 mmol) in THF was added a solution
of vinylmagnesium bromide [prepared from Mg (31 mg,
1.29 mmol) and vinyl bromide (0.136 mL, 1.94 mmol) in
THF (3 mL)] and stirred for 10 min. The reaction was then
quenched with cold saturated aq NH4Cl (5 mL) and extracted
with ether (3Â3 mL). The organic layer was washed with
water and brine, and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column
using ethyl acetate–hexane (1:10) as eluent furnished a z1:1
diastereomeric mixture of the dienol 12a (151 mg, 84%) as
1
oil. IR (Neat): nmax/cmÀ1 3457, 1631, 1594, 917; H NMR
3.7. 3-(2,6-Dimethoxy-3-methylphenyl)-3-methylpent-4-
en-1-ol (13a)
(300 MHz, CDCl3+CCl4, mixture of diastereomers): d 6.98
(1H, d, J 8.4 Hz), 6.64–6.47 (2H, m), 5.81–5.71 (1H, m),
5.10–4.78 (4H, m), 4.04 (1H, br s), 3.75 (3H, s), 3.52 (3H,
s), 2.30–2.03 (2H, m), 2.21 (3H, s), 1.90–1.70 (1H, br s),
1.60 and 1.56 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4,
mixture of diastereomers): d 158.4 (C), 157.6 and 157.5
(C), 150.0 (CH), 142.2 (CH), 129.5 (CH), 127.6 (C), 127.5
and 124.6 (C), 112.9 and 112.7 (CH2), 108.2 and 107.8
(CH), 105.3 and 104.6 (CH2), 71.2 and 70.9 (CH), 60.7
and 60.6 (CH3), 55.5 and 55.3 (CH3), 48.0 and 47.8 (CH2),
44.3 and 44.0 (C), 26.6 and 26.5 (CH3), 16.5 (CH3);
HRMS: m/z calcd for C17H24O3Na (M+Na): 299.1623,
found: 299.1625.
LAH (39 mg, 1.03 mmol) was added to a magnetically
stirred solution of the pentenoate 11a (300 mg, 1.03 mmol)
in dry ether (2 mL) at 0 ꢀC and stirred for 1 h. EtOAc
(1 mL) was carefully added to consume excess reagent and
the reaction was quenched with ice cold water (10 mL).
The solution was then filtered through a sintered funnel
and the residue thoroughly washed with ether (3Â5 mL).
The ether layer was separated, washed with brine, and dried
(Na2SO4). Evaporation of the solvent furnished the primary
alcohol 13a (258 mg, 100%) as oil. IR (Neat): nmax/cmÀ1
3367, 1633, 1594; 1H NMR (300 MHz, CDCl3+CCl4):
d 6.97 and 6.56 (2H, 2Âd, J 8.4 Hz), 6.44 (1H, dd, J 17.4
and 10.5 Hz), 4.88 (1H, d, J 17.4 Hz), 4.79 (1H, d,
J 10.5 Hz), 3.76 (3H, s), 3.50 (3H, s), 3.53–3.47 (2H, m),
3.50 (1H, br s), 2.40–2.10 (2H, m), 2.21 (3H, s), 1.54 (3H,
s); 13C NMR (75 MHz, CDCl3+CCl4): d 158.2 (C), 157.7
3.10. 4-(2,6-Dimethoxy-3-methylphenyl)-4-methylcyclo-
pent-2-enol (15a)
To a magnetically stirred solution of a 1:1 diastereomeric
mixture of the diene 12a (150 mg, 0.60 mmol) in anhydrous

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A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
CH2Cl2 (20 mL) was added a solution of Grubbs’ catalyst
(25 mg, 5 mol %) in CH2Cl2 (10 mL) and stirred at rt for
3 h. Evaporation of the solvent under reduced pressure and
purification of the residue on a silica gel column using ethyl
acetate–hexane (1:5) as eluent furnished a 1:1 diastereomeric
mixture of the enol 15a (133 mg, 100%) as oil. IR (Neat):
nmax/cmÀ1 3410, 1595; 1H NMR (300 MHz, CDCl3+CCl4):
d 6.92 (1H, d, J 8.1 Hz), 6.68 (1H, d, J 5.1 Hz), 6.55 (1H,
d, J 8.1 Hz), 5.65 (1H, m), 4.70–4.90 (1H, m), 3.80 (3H, s),
3.58 and 3.47 (3H, s), 2.74 and 2.54 (1 H, dd, J 14.1 and
7.2 Hz), 2.19 (3H, s), 2.02 (1H, dd, J 14.7 and 4.2 Hz),
1.40 and 1.53 (3H, s), 1.60 (1H, br s); 13C NMR (75 MHz,
CDCl3+CCl4): d 157.3 and 157.2 (C), 156.9 (C), 145.5
and 145.3 (CH), 130.6 and 130.5 (C), 128.9 and 128.7
(CH), 127.2 and 126.8 (CH), 124.0 and 123.9 (C), 107.6
(CH), 60.9 and 60.8 (CH3), 55.4 (CH3), 51.4 and 50.3 (C),
50.8 and 50.2 (CH2), 30.8 and 29.3 (CH3), 16.4 (CH3);
HRMS: m/z calcd for C15H20O3Na (M+Na): 271.1317,
found: 271.1310.
21.6 (CH3), 16.2 (CH3); HRMS: m/z calcd for
C17H22O3Na (M+Na): 275.1647, found: 275.1651.
3.13. 3-(2,6-Dimethoxy-3-methylphenyl)-2,2,3-tri-
methylcyclopentanone (18a)
To activated 10% Pd–C (20 mg) was added a solution of the
enone 17a (180 mg, 0.656 mmol) in ethanol (2 mL) and
stirred for 1 h at rt in an atmosphere of hydrogen created
by evacuative replacement of air (balloon). The catalyst was
then filtered off. Evaporation of the solvent under reduced
pressure furnished the saturated ketone 18a (181 mg,
1
100%) as oil. IR (Neat): nmax/cmÀ1 1734, 1579; H NMR
(300 MHz, CDCl3+CCl4): d 6.97 and 6.51 (2H, 2Âd,
J 8.1 Hz), 3.67 (3H, s), 3.62 (3H, s), 2.45–2.20 (4H, m),
2.22 (3H, s), 1.56 (3H, s), 1.19 (3H, s), 0.69 (3H, s); 13C
NMR (75 MHz, CDCl3+CCl4): d 159.0 (C), 157.4 (C),
129.4 (CH), 124.5 (C), 106.5 (CH), 60.8 (CH3), 54.0
(CH3), 34.9 (CH2), 16.5 (CH3) (other signals are very
broad probably due to fluxional behavior of the molecule);
HRMS: m/z calcd for C17H24O3Na (M+Na): 299.1623,
found: 299.1610.
3.11. 4-(2,6-Dimethoxy-3-methylphenyl)-4-methyl-
cyclopent-2-enone (16a)
To a magnetically stirred suspension of PCC (288 mg,
1.34 mmol) and silica gel (288 mg) in CH2Cl2 (1 mL) was
added a solution of the alcohol 15a (133 mg, 0.54 mmol)
in CH2Cl2 (1 mL) and stirred at rt for 1 h. The reaction mix-
ture was then filtered through a small silica gel column, and
the column was eluted with excess CH2Cl2. Evaporation of
the solvent furnished the enone 16a (123 mg, 93%) as oil.
IR (Neat): nmax/cmÀ1 1711, 1588; 1H NMR (300 MHz,
CDCl3+CCl4): d 8.23 (1H, d, J 5.7 Hz), 6.90 and 6.51 (2H,
2Âd, J 8.4 Hz), 5.93 (1H, d, J 5.7 Hz), 3.76 (3H, s), 3.37
(3H, s), 2.65 and 2.53 (2H, 2Âd, J 18.9 Hz), 2.14 (3H, s),
1.51 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4): d 208.7
(C), 173.7 (CH), 156.9 (C), 156.1 (C), 129.7 (CH), 127.9
(C), 126.8 (CH), 123.8 (C), 107.5 (CH), 61.0 (CH3), 55.5
(CH3), 51.5 (CH2), 46.8 (C), 27.8 (CH3), 16.1 (CH3);
HRMS: m/z calcd for C15H18O3Na (M+Na): 247.1334,
found: 247.1334.
3.14. 3-(2,6-Dimethoxy-3-methylphenyl)-2,2,3-tri-
methylcyclopentanol (19)
To an ice cold magnetically stirred solution of the ketone 18a
(181 mg, 0.66 mmol) in dry methanol (1 mL) was added
NaBH4 (47 mg, 1.31 mmol) and stirred for 5 min. The
solvent was removed under reduced pressure. Water (3 mL)
followed by 3 N aq HCl (4 mL) were added to the reaction
mixture and extracted with ether (3Â3 mL). The combined
ether extract was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate–hexane (1:20–
1:10) as eluent furnished an epimeric mixture of the alcohol
19 (180 mg, 99%) as oil. IR (Neat): nmax/cmÀ1 3411, 1591;
1H NMR (300 MHz, CDCl3+CCl4): d 6.94 and 6.93 (1H, d,
J 8.1 Hz), 6.52 (1H, d, J 8.1 Hz), 3.89–3.76 (1H, m), 3.73
and 3.71 (3H, s), 3.60 (3H, s), 3.05–2.50 (1H, m), 2.16
(3H, s) 2.20–1.26 (4H, m), 1.50 and 1.48 (3H, s), 1.09 and
1.07 (3H, s), 0.66 (3H, s); HRMS: m/z calcd for
C17H26O3Na (M+Na): 301.1780, found: 301.1775.
3.12. 4-(2,6-Dimethoxy-3-methylphenyl)-4,5,5-tri-
methylcyclopent-2-enone (17a)
A solution of the ketone 16a (220 mg, 0.894 mmol) in THF
(1 mL) was added to a suspension of NaH (180 mg, 60% dis-
persion in oil, 4.47 mmol, washed with dry hexanes) in THF
(2 mL) and DMF (0.2 mL) and stirred at rt for 15 min.
Methyl iodide (0.42 mL, 6.7 mmol) was added to the reac-
tion mixture and stirred for 12 h at rt. Water (5 mL) was
added to the reaction mixture and extracted with ether
(3Â5 mL). The ether extract was washed with brine and
dried (Na2SO4). Evaporation of the solvent and purification
of the residue over a silica gel column using ethyl acetate–
hexane (1:10) as eluent furnished the enone 17a (180 mg,
3.15. 4-Methyl-2-(1,2,2-trimethylcyclopentyl)benzene-
1,3-diol dimethyl ether (21a)
To a magnetically stirred suspension of NaH (29 mg, 60%
dispersion in oil, 0.72 mmol) in dry THF (1 mL) was added
a solution of the alcohol 19 (40 mg, 0.144 mmol) in dry THF
(0.5 mL) followed by a catalytic amount of imidazole. The
reaction mixture was heated to 60 ꢀC for 15 min. It was
cooled to rt, added CS2 (0.09 mL, 1.44 mmol), and refluxed
for 15 min. It was cooled to rt, added MeI (0.09 mL,
1.44 mmol), and refluxed for 4 h. It was then cooled to rt,
diluted with water (2 mL), and extracted with ether (3Â
2 mL). The combined organic layer was washed with brine
and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using CH2Cl2–hex-
ane (1:10) as eluent furnished the dithiocarbonate 20 (47 mg,
88%) as yellow oil. IR (Neat): nmax/cmÀ1 1591, 1390, 1375,
1
73%) as oil. IR (Neat): nmax/cmÀ1 1700, 1593; H NMR
(300 MHz, CDCl3+CCl4): d 8.17 (1H, d, J 5.7 Hz), 6.99
and 6.58 (2H, 2Âd, J 7.8 Hz), 5.89 (1H, d, J 5.7 Hz), 3.83
(3H, s), 3.37 (3H, s), 2.21 (3H, s), 1.53 (3H, s), 1.25 (3H,
s), 0.78 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4):
d 214.1 (C), 173.6 (CH), 157.1 (C), 156.8 (C), 129.6 (CH),
126.5 (C), 123.8 (C), 120.6 (CH), 107.0 (CH), 59.9 (CH3),
54.8 (CH3), 54.5 (C), 49.5 (C), 25.2 (CH3), 24.3 (CH3),
1
1240; H NMR (300 MHz, CDCl3+CCl4): d 6.96 and 6.54
(2H, 2Âd, J 8.4 Hz), 5.70–5.50 (1H, m), 3.72 (3H, s), 3.63

A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
9399
and 3.61 (3H, s), 3.26 (1H, br s), 2.56 and 2.51 (3H, s), 2.40–
2.32 (1H, m), 2.23 (3H, s), 1.92–1.42 (5H, m), 1.19 and 1.16
(3H, s), 0.75 (3H, s). A solution of the dithiocarbonate 20
(47 mg, 0.128 mmol), n-Bu3SnH (0.14 mL, 0.512 mmol),
and a catalytic amount of AIBN in dry benzene (2 mL)
was refluxed for 3 h. The reaction mixture was cooled,
diluted with ether (4 mL), washed successively with 1% aq
NH4OH, water, and brine, and dried (Na2SO4). Evaporation
of the solvent under reduced pressure and purification of the
residue on a silica gel column using hexane as eluent fur-
nished the deoxygenated product 21a (25 mg, 75%) as color-
52.2 (C), 45.3 (C), 42.7 (CH2), 40.3 (CH2), 28.5 (CH3),
26.8 (CH3), 22.9 (CH3), 21.7 (CH3), 21.4 (CH2), 16.3
(CH3); HRMS: m/z calcd for C17H24O3Na (M+Na):
299.1623, found: 299.1619.
3.18. Z-(2-Hydroxy-3-methoxy-4-methylphenyl)but-2-
en-1-ol (26)
To a cold (À50 ꢀC) magnetically stirred solution of the cou-
marin14 25 (520 mg, 2.55 mmol) in dry THF (3 mL) was
added LAH (93 mg, 2.5 mmol) in portions and stirred for
30 min. Ethyl acetate (2 mL) was added to the reaction
mixture to consume the excess LAH. The reaction was
then quenched with water (5 mL) and extracted with ether
(3Â5 mL). The combined ether extract was washed with
brine and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl
acetate–hexane (2:5) as eluent furnished the alcohol 26
(488 mg, 92%). IR (Neat): nmax/cmÀ1 3398, 1655, 1616,
1
less oil. IR (Neat): nmax/cmÀ1 1591; H NMR (300 MHz,
CDCl3+CCl4): d 6.91 and 6.50 (2H, 2Âd, J 8.1 Hz), 3.70
(3H, s), 3.58 (3H, s), 3.13 (1H, br s), 2.21 (3H, s), 2.00–
1.90 (1H, m), 1.65–1.40 (4H, m), 1.34 (3H, s), 1.12 (3H,
s), 0.66 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4):
d 158.5 (2C, C), 129.0 (C), 128.7 (CH), 124.4 (C), 106.9
(CH), 61.0 (CH3), 54.5 (CH3), 52.6 (C), 45.4 (C), 43.6
(CH2), 40.3 (CH2), 29.1 (CH3), 27.3 (CH3), 24.1 (CH3),
21.6 (CH2), 16.8 (CH3); HRMS: m/z calcd for C17H26O2K
(M+K): 301.1570, found: 301.1577.
1
1575; H NMR (300 MHz, CDCl3+CCl4): d 6.65 (2H, s),
6.23 (1H, br s), 5.81 (1H, td, J 7.8 and 1.5 Hz), 3.86 (2H,
d, J 7.8 Hz), 3.79 (3H, s), 2.28 (3H, s), 2.20 (1H, br s),
2.03 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4): d 145.6
(C), 145.2 (C), 136.2 (C), 129.6 (C), 127.4 (CH), 126.0
(C), 124.5 (CH), 122.1 (CH), 60.6 (CH2), 60.5 (CH3), 25.2
(CH3), 15.9 (CH3); HRMS: m/z calcd for C12H16O3Na
(M+Na): 231.0997, found: 231.1004.
3.16. 4-Methyl-2-(1,2,2-trimethylcyclopentyl)benzene-
1,3-diol (herbertene-1,5-diol 22)
Methylmagnesium iodide solution in ether (5 mL) was pre-
pared using Mg (50 mg, 2.1 mmol) and CH3I (0.16 mL)
and the solvent was evaporated under vacuum. A solution of
the methyl ether 21a (14 mg, 0.053 mmol) in dry p-cymene
(2 mL) was added to MeMgI and refluxed for 8 h. It was then
cooled to rt, carefully added to cold saturated aq NH4Cl so-
lution (5 mL), and extracted with ether (2Â2 mL). Evapora-
tion of the solvent and purification of the residue on a silica
gel column using ethyl acetate–hexane (1:20) as eluent fur-
nished the diol 22 (8 mg, 64%). IR (Neat): nmax/cmÀ1
3606, 3531, 1605; 1H NMR (300 MHz, CDCl3): d 6.73 and
6.11 (2H, 2Âd, J 7.8 Hz), 4.82 (1H, s), 4.57 (1H, br s),
3.31 (1H, br s), 2.13 (3H, s), 1.80–1.50 (5H, m), 1.49 (3H,
s), 1.18 (3H, s), 0.85 (3H, s); 13C NMR (75 MHz, CDCl3):
d 157.4 (C), 154.8 (C), 128.0 (2C, CH), 115.8 (C), 109.5
(C), 52.3 (C), 46.3 (C), 42.1 (CH2), 40.8 (CH2), 27.7
(CH3), 26.3 (CH3), 24.8 (CH2), 21.8 (CH3), 16.3 (CH3)
(some of the signals arevery broad due to fluxional behavior);
HRMS: m/z calcd for C15H22O2Na (M+Na): 273.1467,
found: 273.1479.
3.19. Z-(2,3-Dimethoxy-4-methylphenyl)but-2-en-1-ol
(8b)
A solution of the diol 26 (320 mg, 1.54 mmol), anhydrous
K2CO3 (425 mg, 3.08 mmol), and CH3I (0.19 mL,
3.08 mmol) in acetone (6 mL) was refluxed for 5 h. Solvent
was evaporated under reduced pressure. The residue was
taken in water and extracted with ether (3Â15 mL). The
ether extract was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue
over a silica gel column using ethyl acetate–hexane (1:5)
as eluent furnished the cinnamyl alcohol 8b (520 mg,
97%). IR (Neat): nmax/cmÀ1 3400; 1H NMR (300 MHz,
CDCl3+CCl4): d 6.85 and 6.67 (2H, 2Âd, J 8.0 Hz), 5.79
(1H, td, J 7.5 and 1.5 Hz), 3.83 (3H, s), 3.79 (2H, d,
J 7.5 Hz), 3.75 (3H, s), 2.25 (3H, s), 2.05 (3 H, s), 2.00
(1 H, br s); 13C NMR (75 MHz, CDCl3+CCl4): d 151.5
(C), 149.8 (C), 136.5 (C), 133.3 (C), 131.4 (C), 127.4
(CH), 125.9 (CH), 124.0 (CH), 60.8 (CH3), 60.6 (CH2),
60.2 (CH3), 25.5 (CH3), 15.9 (CH3); HRMS: m/z calcd for
C13H18O3Na (M+Na): 245.1154, found: 245.1162.
3.17. 3-Hydroxy-4-methyl-2-(1,2,2-trimethylcyclo-
pentyl)phenyl acetate (3)
To a magnetically stirred solution of the diol 22 (6 mg,
0.026 mmol) in CH2Cl2 (0.3 mL) was added sequentially
Ac2O (5 mL, 0.052 mmol), pyridine (50 mL, 0.615 mmol),
and DMAP (1 mg), and stirred at rt for 2 h. Water (1 mL)
was added to the reaction mixture and extracted with
CH2Cl2. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate–hexane
(1:20) as eluent furnished the acetate 3 (5 mg, 71%) as oil.
3.20. Ethyl 3-(2,3-dimethoxy-4-methylphenyl)-
3-methylpent-4-enoate (11b)
A solution of the allyl alcohol 8b (300 mg, 1.35 mmol), tri-
ethyl orthoacetate (1.24 mL, 6.76 mmol), and a catalytic
amount of propionic acid (10 mL) was placed in a sealed
tube and heated to 180 ꢀC for 36 h in an oil bath. Work-up
as described for the ester 11a, followed by purification on a
silica gel column using ethyl acetate–hexane (1:40) as eluent
1
IR (Neat): nmax/cmÀ1 3516, 1749, 1664, 1587; H NMR
(300 MHz, CDCl3): d 6.92 and 6.33 (2H, 2Âd, J 7.8 Hz),
4.88 (1H, br s), 2.90–2.80 (1H, m), 2.24 (3H, s), 2.20 (3H,
s), 1.74–1.51 (5H, m), 1.42 (3H, s), 1.26 (3H, s), 0.79 (3H,
s); 13C NMR (75 MHz, CDCl3): d 170.4 (C), 154.3 (C),
148.7 (C), 128.2 (CH), 126.0 (C), 121.1 (C), 116.3 (CH),
furnished the ester 11b (316 mg, 80%) as oil. IR (Neat): nmax
/
cmÀ1 1734, 1635; 1H NMR (300 MHz, CDCl3+CCl4): d 6.83
and 6.74 (2H, 2Âd, J 8.1 Hz), 6.25 (1H, dd, J 17.4 and
10.8 Hz), 5.02 (1H, dd, J 10.8 and 1.2 Hz), 4.94 (1H, dd,

9400
A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
J 17.4 and 0.9 Hz), 3.92 (2H, q, J 7.5 Hz), 3.83 (3H, s), 3.74
(3H, s), 3.06 and 2.77 (2H, 2Âd, J 14.1 Hz), 2.21 (3H, s), 1.53
(3H, s), 1.05 (3H, t, J 7.5 Hz); 13C NMR (75 MHz,
CDCl3+CCl4): d 171.2 (C), 151.9 (C), 151.7 (C), 146.7
(CH), 136.8 (C), 130.8 (C), 124.3 (CH), 122.2 (CH), 111.0
(CH2), 59.6 (CH3), 59.4 (CH2), 59.2 (CH3), 44.1 (CH2),
42.7 (C), 25.7 (CH3), 15.6 (CH3), 14.1 (CH3); HRMS: m/z
calcd for C17H24O4Na (M+Na): 315.1572, found: 315.1586.
mixture of diastereomers): d 6.88 and 6.87 (1H, d,
J 8.1 Hz), 6.78 and 6.76 (1H, d, J 8.1 Hz), 6.25 and 6.24
(1H, dd, J 17.7 and 10.8 Hz), 5.84–5.69 (1H, m), 5.12–4.89
(4H, m), 4.04 and 3.96 (1H, m), 3.84 and 3.81 (3H, s), 3.74
and 3.73 (3H, s), 2.38–2.25 (1H, m), 2.22 (3H, s), 1.99–
1.89 (1H, m), 1.52 and 1.47 (3H, s), 1.50–1.30 (1H, br s);
13C NMR (75 MHz, CDCl3+CCl4, mixture of diastereo-
mers): d 152.2 (C), 152.11 and 52.08 (C), 148.6 and 148.2
(CH), 142.3 and 142.2 (CH), 137.7 and 137.6 (C), 131.2
and 131.0 (C), 124.9 and 124.7 (CH), 122.6 and 122.4
(CH), 113.3 and 113.1 (CH2), 110.8 (CH2), 70.9 and 70.7
(CH), 59.8 (CH3), 59.4 and 59.3 (CH3), 47.0 and 46.5
(CH2), 43.6 and 43.4 (C), 26.5 and 26.4 (CH3), 15.8 (CH3);
HRMS: m/z calcd for C17H24O3Na (M+Na): 299.1623,
found: 299.1622.
3.21. 3-(2,3-Dimethoxy-4-methylphenyl)-3-methylpent-
4-en-1-ol (13b)
Reduction of the pentenoate 11b (316 mg, 1.08 mmol) with
LAH (40 mg, 1.08 mmol) in dry ether (3 mL) at 0 ꢀC for
30 min and work-up as described for the alcohol 13a, fol-
lowed by purification over silica gel column using ethyl
acetate–hexane (3:7) furnished the alcohol 13b (257 mg,
95%) as oil. IR (Neat): nmax/cmÀ1 3368; 1H NMR
(300 MHz, CDCl3+CCl4): d 6.82 and 6.75 (2H, 2Âd,
J 8.1 Hz), 6.16 (1H, dd, J 17.1 and 10.5 Hz), 5.01 (1H, dd,
J 10.5 and 0.9 Hz), 4.95 (1H, dd, J 17.1 and 0.9 Hz), 3.81
(3H, s), 3.74 (3H, s), 3.60–3.40 (2H, m), 2.42–2.29 (1H,
m), 2.21 (3H, s), 2.05–1.96 (1H, m), 1.42 (3H, s), 1.45 (1H,
br s); 13C NMR (75 MHz, CDCl3+CCl4): d 152.2 (C),
152.0 (C), 147.9 (CH), 137.7 (C), 130.9 (C), 124.7 (CH),
122.3 (CH), 110.7 (CH2), 60.2 (CH2), 59.7 (CH3), 59.3
(CH3), 42.8 (C), 42.2 (CH2), 25.9 (CH3), 15.7 (CH3); HRMS:
m/z calcd for C15H22O3Na (M+Na): 273.1467, found:
273.1470.
3.24. 4-(2,3-Dimethoxy-4-methylphenyl)-4-methyl-
cyclopent-2-en-1-ol (15b)
RCM reaction of a 1:1 diastereomeric mixture of the diene
12b (200 mg, 0.72 mmol) with Grubbs’ catalyst (30 mg,
5 mol %) in CH2Cl2 (30 mL) at rt for 3 h and work-up as de-
scribed for the cyclopentenol 15a, followed by purification
on a silica gel column using ethyl acetate–hexane (1:5) as
eluent furnished a 1:1 diastereomeric mixture of the enol 15b
(180 mg, 100%) as oil. IR (Neat): nmax/cmÀ1 3392, 908; 1H
NMR (300 MHz, CDCl3+CCl4, mixture of diastereomers):
d 6.85–6.65 (2H, m), 6.18 and 6.09 (1H, d, J 5.4 Hz), 5.82
(1H, t, J 5.4 Hz), 4.90–4.75 (1H, m), 3.86 (3H, s), 3.76
(3H, s), 2.58–2.50 (1H, m), 2.21 and 2.20 (3H, s), 1.97
and 1.96 (1H, d, J 14.1 Hz), 1.52 and 1.39 (3H, s); HRMS:
m/z calcd for C15H20O3Na (M+Na): 271.1310, found:
271.1313.
3.22. 3-(2,3-Dimethoxy-4-methylphenyl)-3-methylpent-
4-enal (14b)
Oxidation of the alcohol 13b (250 mg, 1.0 mmol) with PCC
(538 mg, 2.5 mmol) and silica gel (540 mg) in CH2Cl2
(3 mL) at rt for 15 min and work-up as described for the
aldehyde 14a, followed by purification on a silica gel col-
umn using ethyl acetate–hexane (1:20) as eluent furnished
3.25. 4-(2,3-Dimethoxy-4-methylphenyl)-4-methyl-
cyclopent-2-enone (16b)
Oxidation of the alcohol 15b (183 mg, 0.74 mmol) with
PCC (397 mg, 1.84 mmol) and silica gel (400 mg) in
CH2Cl2 (3 mL) at rt for 1 h and work-up as described for
the enone 16a, furnished the enone 16b (179 mg, 96%) as
oil. IR (Neat): nmax/cmÀ1 1715, 1589; 1H NMR (300 MHz,
CDCl3+CCl4): d 7.73 (1H, d, J 5.4 Hz), 6.78 (2H, s), 6.12
(1H, d, J 5.4 Hz), 3.82 (3H, s), 3.75 (3H, s), 2.68 and 2.52
(2H, 2Âd, J 18.3 Hz), 2.22 (3H, s), 1.56 (3H, s); 13C NMR
(75 MHz, CDCl3+CCl4): d 208.6 (C), 170.4 (CH), 152.0
(C), 151.7 (C), 136.4 (C), 131.7 (C), 130.8 (CH), 124.9
(CH), 121.3 (CH), 59.9 (CH3), 59.4 (CH3), 51.0 (CH2),
47.1 (C), 28.4 (CH3), 15.7 (CH3); HRMS: m/z calcd for
C15H19O3 (M+H): 247.1334, found: 247.1335.
the aldehyde 14b (210 mg, 84%) as oil. IR (Neat): nmax
/
1
cmÀ1 2733, 1720, 1681, 1635, 1603; H NMR (300 MHz,
CDCl3+CCl4): d 9.46 (1H, t, J 2.7 Hz), 6.84 and 6.76 (2H,
2Âd, J 7.8 Hz), 6.16 (1H, dd, J 17.4 and 10.5 Hz), 5.08
(1H, d, J 10.5 Hz), 4.98 (1H, d, J 17.4 Hz), 3.82 (3H, s),
3.72 (3H, s), 3.07 (1H, dd, J 15.3 and 2.7 Hz), 2.76 (1H,
dd, J 15.3 and 2.7 Hz), 2.20 (3H, s), 1.51 (3H, s); 13C
NMR (75 MHz, CDCl3+CCl4): d 202.2 (CH), 152.2 (C),
151.9 (C), 146.3 (CH), 136.1 (C), 131.6 (C), 124.9 (CH),
122.2 (CH), 111.8 (CH2), 59.8 (CH3), 59.4 (CH3), 52.2
(CH2), 42.1 (C), 26.4 (CH3), 15.7 (CH3); HRMS: m/z calcd
for C15H20O3Na (M+Na): 271.1310, found: 271.1324.
3.23. 5-(2,3-Dimethoxy-4-methylphenyl)-5-methyl-
hepta-1,6-dien-3-ol (12b)
3.26. 4-(2,3-Dimethoxy-4-methylphenyl)-4,5,5-tri-
methylcyclopent-2-enone (17b)
Grignard reaction of the aldehyde 14b (210 mg, 0.847 mmol)
in THF with vinylmagnesium bromide [prepared from
Mg (41 mg, 1.69 mmol) and vinyl bromide (0.12 mL,
1.69 mmol) in THF (2 mL)] for 10 min at À20 ꢀC and
work-up as described for the dienol 12a, followed by purifi-
cation on a silica gel column using ethyl acetate–hexane
(1:10) as eluent furnished a z1:1 diastereomeric mixture
One-potdialkylationoftheketone16b(100 mg, 0.406 mmol)
with NaH (243 mg, 60%dispersion in oil, 6.09 mmol, washed
with dry hexanes) and methyl iodide (0.51 mL, 8.12 mmol) in
THF (5 mL) and DMF (0.25 mL) for 12 h at rt and work-up as
described for the enone 17a, followed by purification over
asilicagelcolumnusingethylacetate–hexane(1:10)aseluent
furnished the alkylated product 17b (110 mg, 98%) as oil.
IR (Neat): nmax/cmÀ1 1708, 1600; 1H NMR (300 MHz,
CDCl3+CCl4): d 7.87 (1H, d, J 5.7 Hz), 6.80 and 6.70 (2H,
of the dienol 12b (180 mg, 77%) as oil. IR (Neat): nmax
/
1
cmÀ1 3437, 1634, 917; H NMR (300 MHz, CDCl3+CCl4,

A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
9401
2Âd, J 7.8 Hz), 6.06 (1H d, J 5.7 Hz), 3.87 (3H, s), 3.75 (3H,
s), 2.24 (3H, s), 1.47 (3H, s), 1.22 (3H, s), 0.63 (3H, s); 13C
NMR (75 MHz, CDCl3+CCl4): d 214.0 (C), 170.7 (CH),
151.9 (2C, C), 134.6 (C), 131.4 (C), 125.0 (CH), 123.0 (2C,
CH), 60.0 (CH3), 59.3 (CH3), 54.6 (C), 50.9 (C), 26.0 (2C,
CH3), 19.9 (CH3), 15.7 (CH3); HRMS: m/z calcd for
C17H23O3 (M+H): 275.1647, found: 275.1646.
59.3 (CH3), 51.5 (C), 45.0 (C), 41.1 (CH2), 39.3 (CH2),
26.9 (CH3), 25.5 (CH3), 24.1 (CH3), 20.5 (CH2), 15.6
(CH3); HRMS: m/z calcd for C17H26O2Na (M+Na):
285.1830, found: 285.1838.
3.30. 3-(1,2,2-Trimethylcyclopentyl)-6-methylbenzene-
1,2-diol (HM-4 or cuparene-1,2-diol 4)
3.27. 3-(2,3-Dimethoxy-4-methylphenyl)-3,4,4-tri-
methylcyclopentanone (18b)
To a cold (À40 ꢀC) magnetically stirred solution of the
dimethyl ether 21b (40 mg, 0.15 mmol) in dry CH2Cl2
(2 mL) was added drop wise a solution of BBr3 (1 M in
CH2Cl2, 0.86 mL, 0.86 mmol) and stirred at the same tem-
perature for 4 h. The reaction was then quenched with
saturated aq NaHCO3 solution and extracted with CH2Cl2
(3Â3 mL). The combined CH2Cl2 extract was washed
with brine and dried (Na2SO4). Evaporation of the solvent
and purification of the residue over a silica gel column using
ethyl acetate–hexane (1:10) as eluent furnished cuparene-
1,2-diol 4 (22 mg, 62%). IR (Neat): nmax/cmÀ1 3613, 3516,
Hydrogenation of the enone 17b (110 mg, 0.4 mmol) with
10% Pd–C (20 mg) as the catalyst in ethanol (2 mL) for
1 h and work-up as described for the compound 18a, fur-
nished the saturated ketone 18b (111 mg, 100%) as oil. IR
(Neat): nmax/cmÀ1 1738; 1H NMR (300 MHz, CDCl3+
CCl4): d 6.94 and 6.78 (2H, 2Âd, J 8.4 Hz), 3.84 (3H, s),
3.75 (3H, s), 2.70–2.53 (1 H, m), 2.45–2.35 (2H, m), 2.23
(3H, s), 2.07 (1H, ddd, J 12.6, 6.6, and 4.2 Hz), 1.33
(3H, s), 1.23 (3H, s), 0.71 (3H, s); 13C NMR (75 MHz,
CDCl3+CCl4): d 222.1 (C), 152.7 (C), 152.1 (C), 136.8
(C), 130.8 (C), 124.7 (CH), 122.8 (CH), 59.8 (CH3), 59.4
(CH3), 53.4 (C), 49.4 (C), 34.1 (CH2), 32.0 (CH2),
24.5 (CH3), 22.3 (CH3), 20.5 (CH3), 15.6 (CH3); HRMS:
m/z calcd for C17H24O3Na (M+Na): 299.1623, found:
299.1630.
1
1506; H NMR (300 MHz, CDCl3): d 6.74 and 6.53 (2H,
2Âd, J 8.4 Hz), 5.52 (1H, br s), 4.87 (1H, br s), 2.65–2.56
(1H, m), 2.20 (3H, s), 1.85–1.40 (5H, m), 1.40 (3H, s),
1.17 (3H, s), 0.75 (3 H, s); 13C NMR (75 MHz, CDCl3):
d 143.2 (C), 141.9 (C), 131.2 (C), 121.2 (C), 120.7 (CH),
120.5 (CH), 50.9 (C), 44.8 (C), 40.8 (CH2), 39.2 (CH2),
26.7 (CH3), 25.3 (CH3), 22.9 (CH3), 20.2 (CH2), 15.3
(CH3); HRMS: m/z calcd for C15H22O3Na (M+Na):
257.1517, found: 257.1512.
3.28. 7-(2,3-Dimethoxy-4-methylphenyl)-6,6,7-tri-
methyl-1,4-dithiaspiro[4.4]nonane (27)
3.31. 2-Hydroxy-3-(1,2,2-trimethylcyclopentyl)-
6-methylphenyl acetate (HM-3, 28)
To a magnetically stirred solution of the ketone 18b (92 mg,
0.34 mmol) in dry CH2Cl2 (0.3 mL) was added 1,2-ethane-
dithiol (0.28 mL, 1.12 mmol) and iodine (16 mg, 20 mol %)
and stirred at rt for 30 min. To the reaction mixture 1 M aq
Na2S2O3 (2 mL) and 10% aq NaOH (10 mL) were added
and stirred for 5 min, and extracted with CH2Cl2 (2Â4 mL).
The CH2Cl2 extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of
the residue over a silica gel column using CH2Cl2–hexane
(1:10) as eluent furnished the thioketal 27 (94 mg, 80%) as
oil. IR (Neat): nmax/cmÀ1 1397, 1277, 1093, 1057, 1021;
1H NMR (300 MHz, CDCl3+CCl4): d 6.89 and 6.73 (2H,
2Âd, J 8.1 Hz), 3.86 (3H, s), 3.72 (3H, s), 3.30–3.10 (4H,
m), 2.72–2.65 (1H, m), 2.52 (1H, br s), 2.32–2.34 (1H, m),
2.21 (3H, s), 1.76–1.65 (1H, m), 1.54 (3H, s), 1.22 (3H, s),
0.72 (3H, s); HRMS: m/z calcd for C19H28O2S2Na
(M+Na): 375.1428, found: 375.1429.
Acetylation of the diol 4 (15 mg, 0.064 mmol) with Ac2O
(6 mL, 0.064 mmol) and pyridine (5 mL, 0.064 mmol) in
dry CH2Cl2 for 3 h at rt and work-up as described for the ace-
tate 3, followed by purification over a silica gel column using
ethyl acetate–hexane (1:10) as eluent furnished the mono-
acetate 28 (12 mg, 68%) as oil. IR (Neat): nmax/cmÀ1
3406, 1770, 1738, 1618; 1H NMR (300 MHz, CDCl3):
d 7.08 and 6.69 (2H, 2Âd, J 8.4 Hz), 5.18 (1H, s), 2.65–
2.44 (1H, m), 2.37 (3H, s), 2.11 (3H, s), 1.82–1.48 (5H,
m), 1.40 (3H, s), 1.15 (3H, s), 0.74 (3H, s); 13C NMR
(75 MHz, CDCl3): d 168.6 (C), 146.4 (C), 137.9 (C), 132.9
(C), 128.2 (C), 126.2 (CH), 121.0 (CH), 51.2 (C), 44.8
(C), 41.1 (CH2), 39.4 (CH2), 26.8 (CH3), 25.5 (CH3),
22.8 (CH3), 20.6 (CH3), 20.4 (CH2), 16.0 (CH3); HRMS:
m/z calcd for C17H24O3Na (M+Na): 299.1623, found:
299.1636.
3.29. 6-Methyl-3-(1,2,2-trimethylcyclopentyl)benzene-
1,2-diol dimethyl ether (21b)
Acknowledgements
To a magnetically stirred solution of the thioketal 27 (94 mg,
0.267 mmol) in dry ethanol (6 mL) was added Raney nickel
(200 mg, excess) and refluxed for 3 h. The reaction mixture
was cooled and filtered through a short silica gel column us-
ing excess CH2Cl2. Evaporation of the solvent furnished the
We thank the Council of Scientific and Industrial Research,
New Delhi for the award of a research fellowship to P.C.R.
deoxygenated product 21b (70 mg, 100%). IR (Neat): nmax
/
Supplementary data
cmÀ1 1277, 1094, 1054, 1023; 1H NMR (300 MHz,
CDCl3+CCl4): d 6.91 and 6.73 (2H, 2Âd, J 8.1 Hz), 3.81
(3H, s), 3.75 (3H, s), 2.57–2.52 (1H, m), 2.21 (3H, s),
1.85–1.40 (5H, m), 1.35 (3H, s), 1.11 (3H, s), 0.68 (3H, s);
13C NMR (75 MHz, CDCl3+CCl4): d 153.1 (C), 152.1 (C),
138.5 (C), 129.8 (C), 124.2 (CH), 123.6 (CH), 59.9 (CH3),
Copies of the 1H and 13C NMR spectra of cuparene-1,2-diol
(4), HM-3 (revised) (28), and the putative structure of
HM-3 (3). Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.
2006.07.062.

9402
A. Srikrishna, P. C. Ravikumar / Tetrahedron 62 (2006) 9393–9402
F. W. J. Am. Chem. Soc. 1950, 72, 595; (c) Sprenger, R. D.;
Ruoff, P. M. J. Org. Chem. 1946, 11, 189.
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