Total synthesis of (±)-herbertenediol

Article abstract of DOI:10.1016/j.tet.2006.01.021

A formal total synthesis of the sesquiterpene (±)-herbertenediol and its dimers mastigophorenes A-D has been accomplished, starting from vanillin via 2,3-dimethoxy-5-methylbenzaldehyde. A combination of Claisen rearrangement and ring-closing metathesis reactions were employed for the generation of the two vicinal quaternary carbons on a cyclopentane ring.

Full text of DOI:10.1016/j.tet.2006.01.021

Tetrahedron 62 (2006) 2892–2900
Total synthesis of (G)-herbertenediol
*
A. Srikrishna and G. Satyanarayana
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 28 September 2005; revised 3 December 2005; accepted 5 January 2006
Available online 25 January 2006
Abstract—A formal total synthesis of the sesquiterpene (G)-herbertenediol and its dimers mastigophorenes A–D has been accomplished,
starting from vanillin via 2,3-dimethoxy-5-methylbenzaldehyde. A combination of Claisen rearrangement and ring-closing metathesis
reactions were employed for the generation of the two vicinal quaternary carbons on a cyclopentane ring.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of more herbertenoids, herbertenediol 5 and herbertenolide
6 was reported in 1983 by Matsuo and co-workers.4
Liverworts, belonging to the Hepaticae family, are endowed
with a rich and wide variety of mono-, sesqui- and
diterpenoids and/or lipophilic aromatic compounds. An
important endogenous character of the Hepaticae family is
that most of the sesquiterpenoids isolated from liverworts
are enantiomeric to those isolated from the higher plants.1
Several compounds obtained from liverworts show a wide
spectrum of biological properties such as muscle relaxing
activity, antimicrobial, antifungal, 5-lipoxygenase, cyclo-
oxygenase, cytotoxic, insect antifeedant, neurotropic
sprouting, piscicidal, cathepsin B and L, calmodulin
inhibitory and anti-HIV activities. Liverworts from the
genus Herbertus contain herbertane sesquiterpenoids,
which are considered as chemical markers of the genus.2
The herbertane group is a small group of aromatic
sesquiterpenes, isomeric to cuparenes, containing a steri-
cally crowded 1-aryl-1,2,2-trimethylcyclopentane carbon
framework incorporating two vicinal quaternary carbon
atoms on a cyclopentane ring. The first member of this class
of sesquiterpenes, herbertene 1, was isolated in 1981 by
Matsuo and co-workers from the ethyl acetate extract of the
liverwort Herberta adunca (Dicks) Gray.3 In 1982, Matsuo
and co-workers reported the isolation of three phenolic
herbertanes, a-herbertenol 2, a-formylherbertenol 3 and
b-herbertenol 4 along with herbertene 1 and cuparene
sesquiterpenes from the same liverwort.4 Asakawa and co-
workers in 1982 reported the isolation of herbertene 1 and
the phenolic herbertenes, a-herbertenol 2 and b-herbertenol
4 from H. aduncus, H. sakuraii and H. subdetatus. Isolation
In 1988 and 1991 Asakawa and co-workers reported the
isolation of the dimeric herbertanes, mastigophorenes A–D
7–10, dimers of herbertenediol 5, from the liverwort
Mastigophora diclados (Mastigophoraceae).5 The mastigo-
phorenes A–D 7–10 are presumably formed by one electron
oxidative phenolic coupling of herbertenediol 5. Sub-
sequently, isolation of a few other phenolic herbertanes
have been reported.2,6
Keywords: Herbertanes; Mastigophorenes; RCM reaction; Claisen
rearrangement; Vicinal quaternary carbon atoms.
The phenolic herbertanes4–7 have been shown to possess
interesting biological properties such as growth inhibiting
*
Corresponding author. Tel: C91 80 22932215; fax: C91 80 23600529;
e-mail: ask@orgchem.iisc.ernet.in
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.021

A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
2893
activity and antilipid peroxidation activity. Mastigopho-
renes A–D 7–10 were found to exhibit intriguing
neurotropic properties, that is, promote neuronal outgrowth
and enhance choline acetyl transferase activity in the
primary cultures of fetal rat cerebral hemisphere.
Attention was first focused on the synthesis of the aryl
ketone 15 via the bromide 16,14 and vanillin 18 containing
two oxygen atoms on vicinal carbons was chosen as the
suitable starting material, as depicted in Scheme 2. Thus,
bromination of vanillin 18 followed by methylation of
bromovanillin 19 furnished bromoveratraldehyde 20.14
An ionic hydrogenation methodology15 was explored for
the reductive deoxygenation of the aldehyde group in 20.
Reaction of the aldehyde 20 with sodium cyanoborohydride
in the presence of boron trifluoride etherate in refluxing
THF for 10 h gave a 1:2 mixture of the bromoarene 16 and
the benzyl alcohol 21 in 95% yield. Conventional Grignard
and transmetallation reactions failed to couple the bromide
16 with the aldehyde 17. Sonochemically accelerated
Barbier reaction of the bromide 16 with the aldehyde 17
and lithium in THF generated the benzyl alcohol 22 in very
low yield (16%), which on oxidation with PCC and silica
gel in methylene chloride at rt furnished the ketone 15.
The presence of an interesting carbon framework, a
sterically crowded 1-aryl-1,2,2-trimethylcyclopentane, the
difficulty associated with the construction of vicinal
quaternary carbon atoms on a cyclopentane ring, and the
biological properties associated with the phenolic herber-
tanes and mastigophorenes made them challenging
synthetic targets.8,9 Recently, a large number of reports
have appeared on the synthesis of these sesquiterpenes
making them a topic of contemporary interest. Herein, we
describe the formal synthesis of herbertenediol and
mastigophorenes.10
Since the coupling of the bromide 16 with aldehyde 17 was
inefficient, an alternative strategy was investigated for the
synthesis of the ketone 15 via the aldehyde 23 (Scheme 3).
Thus, Clemensen reduction of vanillin 18 with amalgamated
zincgeneratedthephenol24, whichonetherificationwithallyl
bromide furnished the allyl aryl ether 25. Claisen rearrange-
ment of the allyl aryl ether 25, followed by base catalyzed
isomerisation of the double bond in the resultant o-allylphenol
26 generated the phenol16 27. Etherification of the phenol 27
with sodium hydroxide and dimethyl sulfate, followed by
ozonolysis of the double bond in the resultant styrene 28
furnishedthe aldehyde23.17 Grignard reactionofthe aldehyde
23 with isopropylmagnesium bromide in ether for 3 h
furnished the benzyl alcohol 29 in 88% yield, which on
oxidation with pyridinium chlorochromate (PCC) and silica
gel in methylene chloride at rt for 2 h generated the ketone 30.
Reaction of the ketone 30 with sodium hydride and allyl
bromide in refluxing THF for 10 h generated a mixture of the
C-allylated ketone 15 and the allyl enol ether 31, which on
thermal rearrangement at 180 8C in a sealed tube for 30 min
gavethe ketone15in91% yield. The structure ofthe ketone15
was established from its spectral data, in particular the
presenceofacarbonylabsorptionbandat1693 cmK1 intheIR
spectrum, presence of a singlet at d 1.10 in 1H NMR and a two
carbon signal at 24.3 ppm in the 13C NMR for the two
symmetric tertiary methyl groups in addition to other signals.
2. Results and discussion
Olefin metathesis11 is an important reaction in which two
olefins undergo bond reorganization leading to redistribu-
tion of the alkylidene moieties. With the advent of efficient
catalysts, the metathesis reaction has emerged as a powerful
tool, in particular the intramolecular version, that is, ring-
closing metathesis (RCM), for the formation of C–C bonds
in organic synthesis.12 Recently,10 we have developed a
methodology for the total synthesis of a- and b-herbertenols
starting from 2,2-dimethylpent-4-enaldehyde and appro-
priate aryl bromides employing a combination of orthoester
Claisen rearrangement and RCM reactions. Extrapolation of
this methodology has been investigated for the formal total
synthesis of herbertenediol 5 and mastigophorenes A–D
7–10. The retrosynthesis is depicted in Scheme 1. Since
herbertenediol dimethyl ether 11 has already been
transformed into herbertenediol 5 and mastigophorenes
A–D 7–10, it was chosen as the target molecule. It was
envisioned that orthoester Claisen rearrangement13 of the
allyl alcohol 12 followed by RCM reaction of the diene 13
would generate cyclopenteneacetate 14, containing the two
vicinal quaternary carbon atoms, which is a higher
homologue of herbertenediol 5 and could be transformed
into 11 by one carbon degradation. It was thought that the
cinnamyl alcohol 12 could be generated from the ketone 15
employing a Wittig reaction based methodology, and the
ketone 15 could be obtained from the bromide 16 and the
aldehyde 17.
Initially for the conversion of the ketone 15 into the
ciannamyl alcohol 12, Wittig reaction followed by
–
m
–
Scheme 1.

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A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
confirmed the structure of the enynol 33. Controlled
hydrogenation of the acetylene group with Lindlar’s catalyst
in ethanol for 24 h at rt gave the tertiary alcohol 32 in 97%
yield. Reaction of the alcohol 32 with PCC and silica gel in
methylene chloride at rt for 30 h generated the aldehyde 34
in 85% yield, which on regioselective reduction with
sodium borohydirde in methanol at 0 8C for 1.5 h furnished
the alcohol 12 in 75% yield.
The orthoester Claisen rearrangement of the allyl alcohol 12
with triethyl orthoacetate and a catalytic amount of
propionic acid in a sealed tube at 180 8C for 48 h furnished
the g,d-unsaturated ester 13 in 28% yield. The steric
crowding experienced in the transition state in generating a
quaternary centre in-between the already existing quater-
nary centre and the tetrasubstituted aryl group is presumably
the reason for the low yield in the Claisen rearrangement.
Next, the key step in the sequence, RCM reaction of the
diene ester 13 was investigated. RCM reaction of the diene
13 with 7 mol% Grubbs’ first generation catalyst in
methylene chloride furnished the cyclopenteneacetate 14
in 80% yield, whose structure was established from its
spectral data. The absence of signals due to the terminal
olefinic protons and carbons in the NMR spectra, and the
presence of two doublets at d 6.20 and 5.70 due to the
cyclopentene olefinic protons and a high field shifted methyl
singlet at 0.51 (typical for the methyl group cis to the aryl
group in cuparene and herbertenoids) established the
structure of the ester 14. This was further confirmed by
the presence of signals due to four methine and five
quaternary sp2 carbons, and six methyl, three methylene and
two quaternary aliphatic carbons in the 13C NMR spectrum
of the ester 14. Hydrogenation of the olefin in 14 with 10%
palladium on activated charcoal as the catalyst in ethanol
furnished the cyclopentaneacetate 35 in 99% yield.
Scheme 2. (a) Br2, CH2Cl2, 0 8C, 30 min, 98%; (b) K2CO3, MeI, acetone,
reflux, 30 h, 57%; (c) NaCNBH3, BF3$Et2O, THF, reflux, 10 h, 95% (16:21
1:2); (d) Li, THF, 1 h 16%; (e) PCC, silica gel, CH2Cl2, rt, 3 h, 90%.
reduction was considered. As in the case of earlier
examples,10 the Wittig reaction and its Horner–Wads-
worth–Emmons variant failed, presumably due to steric
reasons. Subsequently, a 1,3-transposition methodology18
was contemplated via addition of a vinyl group followed by
rearrangement (Scheme 4). However, reaction of the aryl
ketone 15 with vinylmagnesium bromide failed to generate
the tertiary alcohol 32, and resulted in the replacement of
one of the aromatic methoxy groups with a vinyl group.
Hence, an alternate methodology via the corresponding
acetylene was chosen. Thus, reaction of the ketone 15 with
lithiumacetylide ethylenediamine complex in dry THF for
2 h furnished the tertiary alcohol 33, whose structure was
established from the spectral data. Presence of an absorption
band at 3447 cmK1 due to the hydroxy group in the IR
spectrum; presence of a singlet at d 2.55 in the 1H NMR due
to the acetylenic proton, and two quaternary carbons at 86.4
and 81.6, and a methine at 73.5 due to the propargylic
alcohol part of the compound in addition to other signals
For the conversion of the ester 35 into herbertenol dimethyl
ether 11, degradation of one carbon was required. A three-
step protocol via the aldehyde 36 was explored for the
Scheme 3. (a) Zn, concd HCl, EtOH, reflux, 3 h, 80%; (b) K2CO3, CH2]CHCH2Br, acetone, reflux, 6 h, 95%; (c) sealed tube, 180 8C, 24 h, 90%; (d) KOH,
MeOH, reflux, 10 h, 95%; (e) Me2SO4, NaOH, reflux, 1 h, 96%; (f) O3/O2, CH2Cl2, MeOH, K70 8C; Me2S, rt, 6 h, 80%; (g) i-PrMgBr, Et2O, 0 8C/rt, 3 h,
88%; (h) PCC, silica gel, CH2Cl2, rt, 2 h, 96%; (i) NaH, THF, reflux; CH2ZCHCH2Br, 10 h, 99%; (j) sealed tube, 180 8C, 0.5 h, 92%.

A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
2895
Scheme 4. (a) HC^CLi$(NH2CH2)2, THF, 15–20 8C, 2 h, 90%; (b) H2, Pd–CaCO3, EtOH, 24 h, 97%; (c) PCC, silica gel, CH2Cl2, rt, 30 h, 85%; (d) NaBH4,
MeOH, 0 8C/rt, 1.5 h, 75%; (e) CH3C(OEt)3, EtCOOH, 180 8C, 48 h, 28%; (f) Cl2(PCy3)2RuZCHPh, CH2Cl2, rt, 6 h, 80%; (g) H2 (1 atm), 10% Pd–C,
EtOH, 3 h, 99%.
R
–
Scheme 5. (a) LAH, Et2O, 0 8C, 1 h, 98%; (b) PCC, silica gel, CH2Cl2, rt, 0.5 h, 89%; (c) (Ph3P)3RhCl (20 mol%), C6H6, sealed tube, 120–130 8C, 20 h, 77%;
(d) BBr3, CH2Cl2, K40 8C/rt, 2 h, 98%.
degradation (Scheme 5). Reduction of the ester 35 with
LAH in ether gave the alcohol 37 in 98% yield, which on
oxidation with PCC and silica gel furnished the aldehyde 36.
Wilkinson catalyst mediated decarbonylation of the
aldehyde 36 in benzene at 120–130 8C in a sealed tube for
20 h furnished herbertenediol dimethyl ether 11 in 77%
yield, which exhibited spectral data identical to that of
an authentic sample. Finally, demethylation of the ether 11
with boron tribromide in methlylene chloride furnished
(G)-herbertenediol 5 in 98% yield. Since the dimethyl ether
11 has already been transformed into mastigophorenes A–D
7–10, the present sequence constitutes a formal total
synthesis of these terpenoids.
Claisen rearrangement and ring-closing metathesis reactions
have been employed for the generation of the two vicinal
quaternary carbons on a cyclopentane ring. Even though the
conversion of the alcohol 12 to 13 by the orthoester Claisen
rearrangement is low yielding, it is reasonably compensated
by the high efficiency of the other steps. An overall yield of
6% was obtained for the conversion of the aldehyde 23 into
herbertenediol in 15 steps.
3. Experimental
3.1. General
In conclusion, we have accomplished synthesis of the
sesquiterpene (G)-herbertenediol 5 and its dimers mastigo-
phorenes A–D 7–10 starting from vanillin 18 via 2,3-
dimethoxy-5-methylbenzaldehyde 16. A combination of
IR spectra were recorded on a Jasco FTIR 410 spectropho-
1
tometer. H (300 MHz) and 13C NMR (75 MHz) spectra
were recorded on JNM l-300 spectrometer. The chemical
shifts (d ppm) and coupling constants (Hz) are reported in

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A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
the standard fashion with reference to either internal
tetramethylsilane (for H) or the central line (77.1 ppm) of
(3H, s), 2.31 (3H, s), 2.23 (1H, br s), 2.14 (1H, dd, JZ13.8,
7.5 Hz), 2.05 (1H, dd, JZ13.8, 7.5 Hz), 0.88 (3H, s), 0.81
(3H, s); 13C NMR (75 MHz, CDCl3CCCl4): d 151.8 (C),
144.9 (C), 135.8 (CH), 134.6 (C), 132.3 (C), 121.3 (CH),
117.2 (CH2), 112.2 (CH), 75.5 (CH), 60.4 (CH3), 55.6
(CH3), 43.6 (CH2), 39.4 (C), 23.2 (CH3), 22.5 (CH3), 21.6
(CH3); Mass: m/z 264 (MC, 1%), 182 (13), 181 (100), 153
(55), 151 (25), 138 (17), 123 (13); HRMS: m/z Calcd for
C16H24O3Na (MCNa): 287.1623. Found: 287.1606.
1
CDCl3 (for 13C). NMR samples were prepared using a 1:1
mixture of CDCl3 and CCl4 as solvent. In the 13C NMR
spectra, the nature of the carbons (C, CH, CH2 or CH3) were
determined by recording the DEPT-135 and are given in
parentheses. Low-resolution mass spectra were recorded
using a Shimadzu QP-5050A GCMS instrument using direct
inlet (EI) mode. Relative intensities are given in parenth-
eses. High-resolution mass spectra were recorded on a
Micromass Q-TOF micro mass spectrometer using electron
spray ionization mode. Ozonolysis experiments were
carried out using Fischer 502 ozone generator. The oxygen
flow was adjusted and calibrated to generate 1 mmol of
ozone per 4 min. Acme’s silica gel (100–200 mesh) was
used for column chromatography (approximately 15–20 g
per 1 g of the crude product). Dry THF was obtained by
distillation over sodium-benzophenone ketyl. Dry ether was
obtained by distillation over sodium and stored over sodium
wire. Dry CH2Cl2 was prepared by distilling over calcium
hydride. All the commercial reagents were used as such
without further purification.
3.1.3. 1,2-Dimethoxy-5-methyl-3-(prop-1-enyl)benzene
(28). To a cold (10 8C) magnetically stirred solution of the
phenol 27 (700 mg, 3.93 mmol) in 10% aqueous NaOH
solution (8 mL) was added dimethyl sulfate (0.37 mL,
3.93 mmol) drop-wise. The reaction mixture was refluxed
for 1 h. It was then cooled and extracted with ether
(3!3 mL). The ether extract was washed with brine and
dried (Na2SO4). Evaporation of the solvent followed by
purification over a silica gel column using ethyl acetate–
hexane (1/10) as eluent furnished the methyl ether 28
1
(724 mg, 96%) as an oil.16 IR (neat): nmax/cmK1 1579; H
NMR (300 MHz, CDCl3CCCl4): d 6.76 (1H, s), 6.62 (1H,
dq, JZ16.2, 1.8 Hz), 6.50 (1H, s), 6.14 (1H, dq, JZ16.8,
6.6 Hz), 3.81 (3H, s), 3.72 (3H, s), 2.27 (3H, s), 1.90 (3H,
dd, JZ6.6, 1.8 Hz); 13C NMR (75 MHz, CDCl3CCCl4):
d 152.7 (C), 144.3 (C), 132.9 (C), 131.5 (C), 126.2 (CH),
125.7 (CH), 118.4 (CH), 111.8 (CH), 60.6 (CH3), 55.7
(CH3), 21.6 (CH3), 19.0 (CH3); Mass: (C12H16O2) m/z 192
(MC, 16%), 177 (7), 161 (4), 149 (8), 135 (2), 119 (4), 117
(5), 115 (3), 105 (4), 91 (9), 49 (100).
3.1.1. 3-Bromo-1,2-dimethoxy-5-methylbenzene (16). To
a magnetically stirred solution of the aldehyde 20 (301 mg,
1.23 mmol) in dry THF (5 mL) were added Na(CN)BH3
(387 mg, 6.16 mmol) and BF3$Et2O (1.09 mL, 8.63 mmol)
and refluxed for 10 h. The reaction mixture was cooled to rt;
aqueous NaHCO3 solution (5 mL) was added to the reaction
mixture and extracted with ether (3!3 mL). The combined
organic layer was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue
using ethyl acetate–hexane (1/20) as eluent furnished the
ether 16 (87 mg, 31%) as an oil.14 IR (neat): nmax/cmK1
3.1.4. 2,3-Dimethoxy-5-methylbenzaldehyde (23). A
mixture of dry ozone in oxygen was passed through a cold
(K70 8C) solution of the ether 28 (640 mg, 3.34 mmol) and
a catalytic amount of NaHCO3 in 1:4 methanol/CH2Cl2
(10 mL) for 13 min. The reaction mixture was flushed off
with oxygen to remove excess ozone, and dimethyl sulfide
(1.6 mL) was added to the reaction mixture. It was then
slowly warmed up to rt and magnetically stirred for 8 h.
Evaporation of the solvent under reduced pressure and
purification of the residue on a silica gel column using ethyl
acetate–hexane (1/10) as eluent furnished the aldehyde 23
(477 mg, 80%) as an oil.17 IR (neat): nmax/cmK1 2750, 1693,
1
1598, 1568; H NMR (300 MHz, CDCl3CCCl4): d 6.88
(1H, s), 6.57 (1H, s), 3.81 (3H, s), 3.76 (3H, s), 2.25 (3H, s);
13C NMR (75 MHz, CDCl3CCCl4): d 153.4 (C), 144.5 (C),
134.6 (C), 125.1 (CH), 117.4 (C), 112.6 (CH), 60.3 (CH3),
55.9 (CH3), 21.1 (CH3). Further elution of the column using
ethyl acetate–hexane (1/20) furnished the benzyl alcohol 21
(195 mg, 64%) as an oil.19 IR (neat): nmax/cmK1 3384, 1599,
1
1570; H NMR (300 MHz, CDCl3CCCl4): d 6.94 (1H, s),
6.72 (1H, s), 4.45 (2H, s), 3.78 (3H, s), 3.74 (3H, s), 2.94
(1H, br s).
1
1682, 1607, 1586; H NMR (300 MHz, CDCl3CCCl4): d
10.32 (1H, s), 7.14 (1H, s), 6.89 (1H, s), 3.89 (3H, s), 3.85
(3H, s), 2.30 (3H, s); 13C NMR (75 MHz, CDCl3CCCl4): d
189.6 (CH), 152.6 (C), 150.6 (C), 133.7 (C), 129.3 (C), 119.0
(CH), 118.9 (CH), 62.1 (CH3), 55.8 (CH3), 21.1 (CH3).
3.1.2. 1-(2,3-Dimethoxy-5-methylphenyl)-2,2-dimethyl-
pent-4-en-1-ol (22). To a sonochemically irradiated
suspension of lithium (48 mg, 6.92 mmol) in dry THF
(1 mL) in a round bottom flask, placed in an ultrasonic
cleaning bath, was added a mixture of the aldehyde 17
(77 mg, 0.69 mmol) and the bromoarene 16 (320 mg,
1.38 mmol) in THF (1 mL) at 15–20 8C over a period of
2 min, and sonochemically irradiated for 1 h. Then the
reaction mixture was decanted from the excess lithium,
quenched with saturated aqueous NH4Cl solution (3 mL)
and extracted with ether (3!3 mL). The 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) as eluent furnished
the benzyl alcohol 22 (30 mg, 16%) as an oil. IR (neat):
nmax/cmK1 3470, 1638, 1589; 1H NMR (300 MHz,
CDCl3CCCl4): d 6.70 (1H, s), 6.58 (1H, s), 6.00–5.78
(1H, m), 5.10–5.00 (2H, m), 4.72 (1H, s), 3.83 (3H, s), 3.78
3.1.5. 1-(2,3-Dimethoxy-5-methylphenyl)-2-methyl-
propan-1-ol (29). A solution of isopropylmagnesium
bromide (5.5 mmol), prepared from Mg (152 mg,
6.33 mmol), isopropyl bromide (0.71 mL, 7.6 mmol) and
a catalytic amount of iodine in 3 mL of dry ether, was
added to a cold (0 8C), magnetically stirred solution of
the aldehyde 23 (228 mg, 1.26 mmol) in dry ether (1 mL).
The reaction mixture was slowly warmed up to rt and stirred
for 3 h. It was then poured into saturated aqueous NH4Cl
solution (5 mL) and extracted with ether (3!3 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 (1/20)
as eluent furnished the secondary alcohol 29 (250 mg, 88%)

A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
2897
as an oil. IR (neat): nmax/cmK1 3449, 1590; 1H NMR
(300 MHz, CDCl3CCCl4): d 6.64 (1H, s), 6.57 (1H, s), 4.43
(1H, br s), 3.83 (3H, s), 3.80 (3H, s), 2.29 (3H, s), 2.15 (1H,
s), 2.00–1.80 (1H, m), 1.02 (3H, d, JZ6.6 Hz), 0.79 (3H, d,
JZ6.6 Hz); 13C NMR (75 MHz, CDCl3CCCl4): d 152.1
(C), 144.4 (C), 136.8 (C), 133.1 (C), 120.1 (CH), 112.2
(CH), 75.9 (CH), 60.7 (CH3), 55.6 (CH3), 35.0 (CH), 21.6
(CH3), 19.9 (CH3), 18.7 (CH3); Mass: m/z 224 (MC, 11%),
181 (100), 166 (17), 153 (77), 151 (24), 138 (34), 123 (15),
91 (17); HRMS: m/z Calcd for C13H20O3Na (MCNa):
247.1310. Found: 247.1300.
(1.23 g, 13.3 mmol) in dry THF (1 mL) in a round bottom
flask, placed in an ultrasonic cleaning bath, was added a
solution of the ketone 15 (700 mg, 2.67 mmol) in dry THF
(2 mL) at 15–20 8C over a period of 3 min, and the reaction
mixture was sonochemically irradiated for 2 h. It was then
quenched with saturated aqueous NH4Cl solution (5 mL)
and extracted with ether (3!7 mL). The 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 (1/10) as eluent furnished the
tertiary alcohol 33 (693 g, 90%) as an oil. IR (neat): nmax
/
1
cmK1 3447, 3301, 1637, 1585, 912; H NMR (300 MHz,
CDCl3CCCl4): d 6.93 (1H, s), 6.61 (1H, s), 5.80–5.50 (1H,
m), 4.97 (1H, d, JZ9.9 Hz), 4.96 (1H, d, JZ17.1 Hz), 3.86
(3H, s), 3.82 (3H, s), 2.55 (1H, s), 2.29 (3H, s), 2.29–2.10
(2H, m), 1.23 (1H, br s), 0.91 (3H, s), 0.90 (3H, s); 13C NMR
(75 MHz, CDCl3CCCl4): d 152.0 (C), 145.2 (C), 135.8 (2C,
C and CH), 131.7 (C), 123.6 (CH), 117.4 (CH2), 112.9 (CH),
86.4 (C), 81.6 (C), 73.5 (CH), 61.3 (CH3), 55.7 (CH3), 44.1
(C), 41.2 (CH2), 22.0 (CH3), 21.6 (CH3), 21.5 (CH3); Mass:
m/z 273 (MCKMe, 2%), 205 (100), 191 (14), 190 (33),
179 (29), 121 (10); HRMS: m/z Calcd for C18H24O3Na
(MCNa): 311.1623. Found: 311.1618.
3.1.6. 1-(2,3-Dimethoxy-5-methylphenyl)-2-methyl-
propan-1-one (30). To a magnetically stirred suspension
of PCC (721 mg, 3.34 mmol) and silica gel (721 mg) in dry
CH2Cl2 (1 mL) was added a solution of the sec-alcohol 29
(250 mg, 1.11 mmol) in CH2Cl2 (1 mL) and stirred
vigorously for 2 h at rt. The reaction mixture was then
filtered through a small silica gel column, and the column
eluted with more CH2Cl2. Evaporation of the solvent
furnished the ketone 30 (238 mg, 96%) as an oil. IR
1
(neat): nmax/cmK1 1693, 1603, 1586; H NMR (300 MHz,
CDCl3CCCl4): d 6.70 (1H, s), 6.67 (1H, s), 3.80 (3H, s),
3.74 (3H, s), 3.26 (1H, septet, JZ6.9 Hz), 2.26 (3H, s), 1.08
(6H, d, JZ6.9 Hz); 13C NMR (75 MHz, CDCl3CCCl4): d
207.4 (C), 152.4 (C), 145.0 (C), 134.4 (C), 133.5 (C), 120.6
(CH), 115.5 (CH), 61.4 (CH3), 55.7 (CH3), 40.1 (CH), 21.2
(CH3), 18.6 (2C, CH3); Mass: m/z 222 (MC, 10%), 207 (4),
180 (12), 179 (100), 136 (17), 91 (15); HRMS: m/z Calcd for
C13H18O3Na (MCNa): 245.1154. Found: 245.1146.
3.1.9. 3-(2,3-Dimethoxy-5-methylphenyl)-4,4-dimethyl-
hept-6-en-3-ol (32). To activated Lindlar’s catalyst
(200 mg) was added a solution of the enynol 33 (500 mg,
1.73 mmol) in ethanol (2 mL). The reaction mixture was
stirred for 24 h at rt in an atmosphere of hydrogen, created
by evacuative replacement of air (balloon), and then the
catalyst was filtered off. Evaporation of the solvent
furnished the dienol 32 (488 mg, 97%) as an oil. IR
(neat): nmax/cmK1 3475, 1637, 1583, 914; 1H NMR
(300 MHz, CDCl3CCCl4): 6.70 (1H, dd, JZ16.8,
10.5 Hz), 6.67 (1H, s), 6.57 (1H, s), 5.76 (1H, ddt,
JZ18.0, 9.0, 7.5 Hz), 5.46 (1H, d, JZ16.8 Hz), 5.17 (1H,
d, JZ10.5 Hz), 4.95 (1H, d, JZ9.0 Hz), 4.94 (1H, d,
JZ18.0 Hz), 4.60 (1H, br s), 3.82 (6H, s), 2.32 (3H, s),
2.15–1.95 (2H, m), 0.84 (6H, s); 13C NMR (75 MHz,
CDCl3CCCl4): d 152.4 (C), 145.2 (C), 141.6 (CH), 136.4
(CH), 135.9 (C), 131.6 (C), 122.9 (CH), 117.1 (CH2), 113.9
(CH2), 112.1 (CH), 82.2 (C), 61.1 (CH3), 55.7 (CH3), 42.8
(C), 41.4 (CH2), 22.4 (CH3), 22.0 (CH3), 21.8 (CH3); Mass:
m/z 207 (MCKC6H11, 73%), 175 (12); HRMS: m/z Calcd
for C18H26O3Na (MCNa): 313.1780. Found: 313.1770.
3.1.7. 1-(2,3-Dimethoxy-5-methylphenyl)-2,2-dimethyl-
pent-4-en-1-one (15). To a magnetically stirred suspension
of NaH (234 mg, 60% dispersion in oil, 5.85 mmol, washed
with dry hexanes) in dry THF (1 mL) was added a solution
of the ketone 30 (260 mg, 1.17 mmol) in dry THF (2 mL)
and stirred for 40 min at rt. Allyl bromide (0.5 mL,
5.85 mmol) was added to the reaction mixture and stirred
for 10 h at rt. It was then quenched with water (5 mL) and
extracted with ether (3!4 mL). The combined 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 (1/20) as eluent
furnished a mixture of O-allylated and C-allylated
compounds (31 and 15), which was taken into a sealed
tube (neat) and heated at 180 8C for 30 min. Purification of
the reaction mixture over a silica gel column using ethyl
acetate–hexane (1/20) as eluent furnished the ketone 15
(279 mg, 91%) as an oil. IR (neat): nmax/cmK1 1693, 1639,
3.1.10. 3-(2,3-Dimethoxy-5-methylphenyl)-4,4-dimethyl-
hepta-2,6-dienal (34). To a magnetically stirred suspension
of PCC (3.62 g, 16.8 mmol) and silica gel (3.62 g) in dry
CH2Cl2 (10 mL) was added a solution of the tertiary alcohol
32 (488 mg, 1.68 mmol) in CH2Cl2 (2 mL) and stirred
vigorously for 30 h at rt. The reaction mixture was then
filtered through a small silica gel column, and the column
eluted with more 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 enal 34
(412 mg, 85%) as an oil. IR (neat): nmax/cmK1 2748, 1676,
1
1588; H NMR (300 MHz, CDCl3CCCl4): d 6.62 (1H, s),
6.31 (1H, s), 5.85–5.60 (1H, m), 5.10–4.90 (2H, m), 3.79
(3H, s), 3.66 (3H, s), 2.26 (3H, s), 2.35–2.25 (2H, m), 1.10
(6H, s); 13C NMR (75 MHz, CDCl3CCCl4): d 211.4 (C),
152.1 (C), 142.4 (C), 136.5 (C), 134.4 (CH), 133.4 (C),
117.8 (CH2), 117.6 (CH), 113.3 (CH), 61.2 (CH3), 55.4
(CH3), 47.7 (C), 43.8 (CH2), 24.3 (2C, CH3), 21.3 (CH3);
Mass: m/z 262 (MC, 3%), 180 (11), 179 (100), 136 (8), 91
(8); HRMS: m/z Calcd for C16H22O3Na (MCNa):
285.1467. Found: 285.1452.
1
1638, 1583, 916; H NMR (300 MHz, CDCl3CCCl4): d
9.25 (1H, d, JZ8.1 Hz), 6.68 (1H, s), 6.37 (1H, s), 6.15 (1H,
d, JZ8.1 Hz), 5.85–5.65 (1H, m), 5.07 (1H, d, JZ9.0 Hz),
5.04 (1H, d, JZ16.2 Hz), 3.87 (3H, s), 3.68 (3H, s), 2.32
(3H, s), 2.24 (2H, d, JZ6.9 Hz), 1.13 (3H, s), 1.07 (3H, s);
13C NMR (75 MHz, CDCl3CCCl4): d 193.5 (CH), 171.0
3.1.8. 3-(2,3-Dimethoxy-5-methylphenyl)-4,4-dimethyl-
hept-6-en-1-yn-3-ol (33). To a sonochemically irradiated
suspension of lithiumacetylide ethylenediamine complex

2898
A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
(C), 152.3 (C), 144.0 (C), 134.5 (CH), 132.8 (C), 130.9 (C),
128.5 (CH), 121.9 (CH), 117.9 (CH2), 112.9 (CH), 60.1
(CH3), 55.4 (CH3), 45.8 (CH2), 40.7 (C), 26.9 (CH3), 26.7
(CH3), 21.3 (CH3); Mass: m/z 288 (MC, 10%), 259 (64), 257
(100), 216 (63), 189 (39), 173 (20); HRMS: m/z Calcd for
C18H24O3Na (MCNa): 311.1623. Found: 311.1619.
anhydrous CH2Cl2 (13 mL) was added a solution of Grubbs’
catalyst (21 mg, 7 mol%) in anhydrous CH2Cl2 (10 mL) and
the reaction mixture was stirred at rt for 6 h. Evaporation of
the solvent under reduced pressure and purification of
the residue on a silica gel column using ethyl acetate–
hexane (1/30) as eluent furnished the cyclopentene ester 14
(67 mg, 80%) as an oil. IR (neat): nmax/cmK1 1738, 1584;
1H NMR (300 MHz, CDCl3CCCl4): d 6.59 (1H, s), 6.54
(1H, s), 6.20 (1H, d, JZ6.0 Hz), 5.70 (1H, d, JZ6.0 Hz),
3.92 (2H, q, JZ7.2 Hz), 3.81 (3H, s), 3.80 (3H, s), 3.51 (1H,
d, JZ15.3 Hz), 2.39 (1H, d, JZ15.3 Hz), 2.34 (1H, d, JZ
16.5 Hz), 2.26 (3H, s), 2.13 (1H, dd, JZ16.5, 1.5 Hz), 1.25
(3H, s), 0.51 (3H, s), 1.06 (3H, t, JZ7.2 Hz); 13C NMR
(75 MHz, CDCl3CCCl4): d 172.2 (C), 152.4 (C), 146.1 (C),
139.6 (CH), 134.9 (C), 131.4 (C), 127.2 (CH), 122.1 (CH),
111.9 (CH), 60.0 (CH3), 59.5 (CH2), 58.8 (C), 55.6 (CH3),
48.4 (CH2), 45.7 (C), 41.1 (CH2), 28.5 (CH3), 24.4 (CH3),
21.7 (CH3), 14.2 (CH3); Mass: m/z 332 (MC, 62%), 258
(52), 245 (86), 243 (58), 215 (100), 189 (45), 185 (41), 175
(43), 149 (69), 115 (50), 91 (66); HRMS: m/z Calcd for
C20H28O4Na (MCNa): 355.1885. Found: 355.1883.
3.1.11. 3-(2,3-Dimethoxy-5-methylphenyl)-4,4-dimethyl-
hepta-2,6-dien-1-ol (12). To an ice cold, magnetically
stirred solution of the aldehyde 34 (360 mg, 1.25 mmol) in
dry methanol (3 mL) was added NaBH4 (47.5 mg,
1.25 mmol) and stirred for 90 min at the same temperature.
The solvent was removed under reduced pressure, diluted
with water (5 mL) followed by quenched with 3 N aqueous
HCl (5 mL) and extracted with CH2Cl2 (5!6 mL). The
combined CH2Cl2 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 the primary alcohol 12
(271 mg, 75%) as an oil. IR (neat): nmax/cmK1 3423, 1638,
1583, 911; 1H NMR (300 MHz, CDCl3CCCl4): d 6.56 (1H,
s), 6.26 (1H, s), 5.95–5.60 (2H, m), 5.00–4.90 (2H, m), 3.79
(3H, s), 3.68 (3H, s), 3.80–3.40 (2H, m), 2.24 (3H, s),
2.24–2.00 (2H, m), 1.98 (1H, br s), 1.02 (3H, s), 0.96 (3H, s);
13C NMR (75 MHz, CDCl3CCCl4): d 152.2 (C), 147.8 (C),
143.9 (C), 135.9 (CH), 132.8 (C), 132.4 (C), 125.7 (CH),
122.8 (CH), 116.8 (CH2), 112.1 (CH), 60.8 (CH2), 60.2
(CH3), 55.4 (CH3), 46.1 (CH2), 38.8 (C), 27.7 (CH3), 27.3
(CH3), 21.3 (CH3); Mass: m/z 290 (MC, 42%), 260 (44), 249
(39), 231 (69), 207 (85), 205 (75), 179 (87), 175 (98), 165
(80), 151 (65), 115 (50), 97 (80), 91 (80); HRMS: m/z Calcd
for C18H26O3Na (MCNa): 313.1780. Found: 313.1787.
3.1.14. Ethyl 2-[1-(2,3-dimethoxy-5-methylphenyl)-2,2-
dimethylcyclopent-1-yl]acetate (35). To an activated 5%
Pd–C (15 mg) was added a solution of the ester 14 (35 mg,
0.10 mmol) in ethanol (1 mL). The reaction mixture was
stirred for 3 h at rt in an atmosphere of hydrogen, created by
evacuative replacement of air (balloon), and then the
catalyst was filtered off. Evaporation of the solvent
furnished the cyclopentane ester 35 (35 mg, 99%) as an
oil. IR (neat): nmax/cmK1 1737, 1582; 1H NMR (300 MHz,
CDCl3CCCl4): d 6.59 (1H, s), 6.54 (1H, s), 3.87 (2H,
q, JZ6.9 Hz), 3.80 (3H, s), 3.77 (3H, s), 3.42 and 2.37
(2H, 2!d, JZ15.3 Hz), 2.85–2.50 (1H, m), 2.26 (3H, s),
2.15–2.00 (1H, m), 1.85–1.65 (2H, m), 1.54 (1H, d,
JZ9.0 Hz), 1.51 (1H, d, JZ6.9 Hz), 1.10 (3H, s), 1.01
(3H, t, JZ6.9 Hz), 0.64 (3H, s); 13C NMR (75 MHz,
CDCl3CCCl4): d 172.2 (C), 152.4 (C), 146.8 (C), 136.0 (C),
130.9 (C), 122.2 (CH), 112.0 (CH), 59.9 (CH3), 59.2 (CH2),
55.6 (CH3), 53.8 (C), 46.1 (C), 41.1 (CH2), 39.4 (CH2), 36.3
(CH2), 27.3 (CH3), 25.7 (CH3), 21.9 (CH3), 20.8 (CH2), 14.3
(CH3); Mass: m/z 334 (MC, 68%), 252 (100), 219 (41), 189
(61), 172 (53), 165 (35), 149 (70); HRMS: m/z Calcd for
C20H30O4Na (MCNa): 357.2042. Found: 357.2056.
3.1.12. Ethyl 3-vinyl-3-(2,3-dimethoxy-5-methylphenyl)-
4,4-dimethylhept-6-enoate (13). A solution of the allyl
alcohol 12 (244 mg, 0.84 mmol), triethyl orthoacetate
(1.53 mL, 8.41 mmol) and a catalytic amount of propionic
acid was placed in a sealed tube and heated to 180 8C for
2 days in an oil bath. The reaction mixture was then cooled,
diluted with ether (5 mL), washed with 3 N aqueous HCl
(5 mL) followed by saturated 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 diene ester 13
(85 mg, 28%) as an oil. IR (neat): nmax/cmK1 1746, 1637,
1582, 911; 1H NMR (300 MHz, CDCl3CCCl4): d 6.84 (1H,
dd, JZ18.0, 10.4 Hz), 6.61 (1H, s), 6.57 (1H, s), 5.85–5.55
(1H, m), 5.12 (1H, d, JZ11.1 Hz), 5.04 (1H, d, JZ
17.4 Hz), 5.00–4.85 (2H, m), 3.97 (2H, q, JZ6.9 Hz), 3.81
(3H, s), 3.68 (3H, s), 2.79 (1H, d, JZ17.4 Hz), 2.26 (3H, s),
2.30–1.90 (3H, m), 1.14 (3H, t, JZ6.9 Hz), 0.83 (6H, s); 13C
NMR (75 MHz, CDCl3CCCl4): d 171.8 (C), 152.6 (C),
147.1 (C), 142.1 (2C, C and CH), 136.0 (CH), 130.3 (C),
123.8 (CH), 117.3 (CH2), 114.0 (CH2), 111.7 (CH), 60.2
(CH3), 55.6 (CH3), 59.5 (CH2), 53.0 (C), 41.9 (CH2), 41.4
(C), 37.4 (CH2), 22.7 (2C, CH3), 21.8 (CH3), 14.3 (CH3);
Mass: m/z 360 (MC, 1%), 278 (42), 231 (20), 203 (100), 189
(28), 173 (18); HRMS: m/z Calcd for C22H32O4Na (MC
Na): 383.2198. Found: 383.2211.
3.1.15.
2-[1-(2,3-Dimethoxy-5-methylphenyl)-2,2-
dimethylcyclopent-1-yl]ethanol (37). To a cold (0 8C),
magnetically stirred solution of the ester 35 (20 mg,
0.06 mmol) in 1 mL of dry ether was added LiAlH4
(11.37 mg, 0.29 mmol) and stirred for 1 h. The reaction
mixture was then diluted with ether (3 mL) and carefully
quenched with two drops of water. The organic layer was
separated and the aqueous phase was extracted with ether
(3!2 mL). The combined organic phase 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 (1/10–1/5) as eluent furnished the
primary alcohol 37 (17 mg, 98%). IR (neat): nmax/cmK1
1
3363, 1579; H NMR (300 MHz, CDCl3CCCl4): d 6.57
(1H, s), 6.54 (1H, s), 3.81 (3H, s), 3.78 (3H, s), 3.45 (1H, td,
JZ9.6, 5.7 Hz), 3.30 (1H, td, JZ9.6, 5.4 Hz), 2.70–2.30
(2H, m), 2.26 (3H, s), 2.00–1.80 (1H, m), 1.80–1.40 (6H,
m), 1.34 (3H, s), 0.66 (3H, s); 13C NMR (75 MHz, CDCl3C
3.1.13. Ethyl 2-[1-(2,3-dimethoxy-5-methylphenyl)-5,5-
dimethylcyclopent-2-enyl]acetate (14). To a magnetically
stirred solution of the diene ester 13 (130 mg, 0.36 mmol) in

A. Srikrishna, G. Satyanarayana / Tetrahedron 62 (2006) 2892–2900
2899
CCl4): d 152.6 (C), 146.9 (C), 136.7 (C), 131.5 (C), 122.1
(CH), 111.7 (CH), 61.6 (CH2), 60.1 (CH3), 55.6 (CH3), 53.9
(C), 45.9 (C), 40.8 (CH2), 37.3 (CH2), 29.8 (CH2), 27.1
(CH3), 25.5 (CH3), 21.7 (CH3), 20.9 (CH2); Mass: m/z 292
(MC, 74%), 210 (100), 207 (30), 191 (45), 179 (66), 166
(61), 165 (50), 149 (62), 115 (33), 105 (31), 91 (57); HRMS:
m/z Calcd for C18H28O3Na (MCNa): 315.1936. Found:
315.1925.
(1/10) as eluent furnished herbertenediol 5 (7 mg, 98%).
IR (neat): nmax/cmK1 3526, 1599; 1H NMR (300 MHz,
CDCl3CCCl4): d 6.68 (1H, s), 6.56 (1H, s), 5.39 (1H, s),
5.23 (1H, br s), 2.70–2.59 (1H, m), 2.22 (3H, s), 1.82–1.43
(5H, m), 1.41 (3H, s), 1.18 (3H, s), 0.76 (3H, s); 13C NMR
(75 MHz, CDCl3CCCl4): d 143.5 (C), 141.2 (C), 133.6 (C),
128.4 (C), 122.0 (CH), 113.6 (CH), 51.3 (C), 45.0 (C), 41.1
(CH2), 39.4 (CH2), 27.0 (CH3), 25.6 (CH3), 23.0 (CH3), 21.3
(CH3), 20.4 (CH2); Mass: m/z 234 (MC, 43%), 164 (40), 152
(85), 151 (100).
3.1.16.
2-[1-(2,3-Dimethoxy-5-methylphenyl)-2,2-
dimethylcyclopent-1-yl]acetaldehyde (36). To a magneti-
cally stirred suspension of PCC (62.7 mg, 0.29 mmol) and
silica gel (62.7 mg) in dry CH2Cl2 (0.5 mL) was added a
solution of the primary alcohol 37 (17 mg, 0.06 mmol) in
CH2Cl2 (0.5 mL) and stirred vigorously for 30 min at rt. The
reaction mixture was then filtered through a small silica gel
column, and the column eluted with more CH2Cl2.
Evaporation of the solvent furnished the aldehyde 36
(15 mg, 89%) as an oil, which was found to decompose
Acknowledgements
We thank the Council of Scientific and Industrial Research,
New Delhi for the award of a research fellowship to G.S.
References and notes
1
slowly. IR (neat): nmax/cmK1 2729, 1719, 1579; H NMR
1. Asakawa, Y. In Herz, W., Kirby, W. B., Moore, R. E.,
Steglich, W., Tamm, Ch., Eds.; Progress in the Chemistry of
Organic Natural Products; Springer: Wien, New York, 1995;
Vol. 65, pp 1–296.
(300 MHz, CDCl3CCCl4): d 9.43 (1H, t, JZ3.0 Hz), 6.69
(1H, s), 6.66 (1H, s), 3.83 (3H, s), 3.79 (3H, s), 3.50 (1H, d,
JZ16.2 Hz), 2.83–2.62 (1H, m), 2.39 (1H, dd, JZ16.2,
3.0 Hz), 2.29 (3H, s), 1.95–1.68 (5H, m), 1.11 (3H, s), 0.69
(3H, s); 13C NMR (75 MHz, CDCl3CCCl4): d 205.3 (CH),
152.7 (C), 146.4 (C), 135.1 (C), 132.0 (C), 121.9 (CH),
112.1 (CH), 60.1 (CH3), 55.6 (CH3), 52.7 (C), 48.4 (CH2),
45.8 (C), 40.5 (CH2), 36.6 (CH2), 26.5 (CH3), 25.3 (CH3),
21.6 (CH3), 20.5 (CH2).
2. Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y.
Phytochemistry 2000, 55, 247.
3. Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Chem.
Commun. 1981, 864.
4. (a) Matsuo, A.; Yuki, S.; Nakayama, M.; Hayashi, S. Chem.
Lett. 1982, 463. (b) Matsuo, A.; Nakayama, N.; Nakayama, M.
Phytochemistry 1985, 24, 777. (c) Matsuo, A.; Yuki, S.;
Nakayama, M. J. Chem. Soc., Perkin Trans. 1 1986, 701.
(d) Matsuo, A.; Yuki, S.; Nakayama, M. Chem. Lett. 1983, 1041.
(e) Asakawa, Y.; Matsuda, R.; Schofield, W. B.; Gradstein, S. R.
Phytochemistry 1982, 21, 2471.
3.1.17. 1-(2,3-Dimethoxy-5-methylphenyl)-1,2,2-tri-
methylcyclopentane (11). Wilkinson catalyst (23 mg,
0.025 mmol) was added to a solution of the aldehyde 36
(15 mg, 0.05 mmol) in dry benzene (0.5 mL) and heated at
120–130 8C for 20 h in a sealed tube. Evaporation of the
solvent under reduced pressure followed by purification on a
silica gel column using ethyl acetate–hexane (1/30) as eluent
furnished herbertenediol dimethyl ether 11 (9 mg, 77% based
5. (a) Fukuyama, Y.; Toyota, M.; Asakawa, Y. J. Chem. Soc.,
Chem. Commun. 1988, 1341. (b) Fukuyama, Y.; Asakawa, Y.
J. Chem. Soc., Perkin Trans. 1 1991, 2737. (c) Nagashima, F.;
Nishioka, E.; Kameo, K.; Nakagawa, C.; Asakawa, Y.
Phytochemistry 1991, 30, 215. (d) Asakawa, Y.; Lin, X.;
Kondo, K.; Fukuyama, Y. Phytochemistry 1991, 30, 4019.
(e) Toyota, M.; Koyama, H.; Asakawa, Y. Phytochemistry
1997, 46, 145.
1
on consumed aldehyde 36). IR (neat): nmax/cmK1 1580; H
NMR (300 MHz, CDCl3CCCl4): d 6.75 (1H, s), 6.62 (1H, s),
3.85 (3H, s), 3.77 (3H, s), 2.70–2.50 (1H, m), 2.30 (3H, s),
1.85–1.30 (5H, m), 1.36 (3H, s), 1.12 (3H, s), 0.70 (3H, s);
13C NMR (75 MHz, CDCl3CCCl4): d 153.0 (C), 146.6 (C),
140.1 (C), 131.6 (C), 121.6 (CH), 111.0 (CH), 60.4 (CH3),
55.6 (CH3), 51.5 (C), 45.0 (C), 40.8 (CH2), 38.9 (CH2), 26.8
(CH3), 25.2 (CH3), 24.1 (CH3), 21.7 (CH3), 20.3 (CH2);
Mass: m/z 262 (MC, 29%), 257 (25), 180 (52), 179 (20), 165
(13), 149 (9); HRMS: m/z Calcd for C17H26O2Na (MCNa):
285.1830. Found: 285.1831. Further elution of the column
with ethyl acetate–hexane (1/30) as eluent furnished the
unreacted aldehyde 36 (2 mg).
6. (a) Buchanan, M. S.; Connolly, J. D.; Rycroft, D. S.
Phytochemistry 1996, 43, 1245. (b) Feld, H.; Zapp, J.;
Becker, H. Phytochemistry 2003, 64, 1335.
7. (a) Fukuyama, Y.; Otoshi, Y.; Kodama, M.; Hasegawa, T.;
Okazaki, H. TetrahedronLett. 1990, 31, 4477. (b)Hashimoto, T.;
Irita, H.; Takaoka, S.; Tanaka, M.; Asakawa, Y. Tetrahedron
2000, 56, 3153. (c) Asakawa, Y. Phytochemistry 2001, 56, 297.
8. For the first synthesis of phenolic herbertenes, see: Eicher, T.;
Servet, F.; Speicher, A. Synthesis 1996, 863. For other
syntheses, see: Srikrishna, A.; Lakshmi, B. V. Tetrahedron
Lett. 2005, 46, 4879 and references cited therein.
3.1.18. 1-(2,3-Dihydroxy-5-methylphenyl)-1,2,2-tri-
methylcyclopentane [(G)-herberenediol 5]. A solution
of BBr3 (1 M in CH2Cl2, 0.30 mL, 0.30 mmol) was added
drop-wise to a magnetically stirred solution of the ether 11
(8 mg, 0.03 mmol) in CH2Cl2 (2 mL) at K40 8C. The
reaction mixture slowly warmed up to rt and stirred for 2 h
at rt. It was then quenched with saturated aqueous NaHCO3
solution (1 mL) and extracted with CH2Cl2 (3!2 mL). The
combined organic layer 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
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