Synthesis of (±)-12-methoxyherbertenediol dimethyl ether

Article abstract of DOI:10.1080/00397910701574577

Efficient total synthesis of (±)-12-methoxyherbertenediol dimethyl ether and 12-homoherbertenediol was accomplished starting from vanillin employing a Claisen rearrangement-RCM reaction-based approach. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701574577

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Synthesis of (±)‐12‐Methoxyherbertenediol
Dimethyl Ether
A. Srikrishna a , S. Ratna Kumar a & P. C. Ravikumar a
a Department of Organic Chemistry , Indian Institute of Science , Bangalore,
India
Published online: 10 Dec 2007.
To cite this article: A. Srikrishna , S. Ratna Kumar & P. C. Ravikumar (2007) Synthesis of
(±)‐12‐Methoxyherbertenediol Dimethyl Ether, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:23, 4123-4140, DOI: 10.1080/00397910701574577
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Synthetic Communicationsw, 37: 4123–4140, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701574577
Synthesis of (+)-12-Methoxyherbertenediol
Dimethyl Ether
A. Srikrishna, S. Ratna Kumar, and P. C. Ravikumar
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
Abstract: Efficient total synthesis of (+)-12-methoxyherbertenediol dimethyl ether
and 12-homoherbertenediol was accomplished starting from vanillin employing a
Claisen rearrangement–RCM reaction–based approach.
Keywords: metathesis, natural products, rearrangement, ring closure, total synthesis
The herbertane group[1] is a small group of aromatic sesquiterpenes, isomeric to
cuparanes, containing a sterically crowded 1-aryl-1,2,2-trimethylcyclopentane
carbonframework incorporating two vicinal quaternarycarbon atoms ona cyclo-
pentane ring. Even though cuparene 1, isomeric to herbertane, has been known[2]
since 1958, the herbertane family of sesquiterpenes was reported only in the
1980s. Isolation of the first member of the family, herbertene 2, was reported
in 1981 by Matsuo and coworkers from the ethyl acetate extract of the
liverwort Herberta adunca (Dicks) S. Gray belonging to the family herberta-
ceae.[3] Subsequently, a few other phenolic herbertanes 3–9 were isolated
from a variety of Herbertus sources, (Fig. 1).[4] In 2000, Asawaka and
coworkers reported[5] the isolation of seven herbertenes: herbertene-acetal 10,
herbertene-1,14-diol 11, herbertene-1,15-diol 12, herbertene-1,13-diol 13, her-
bertenones A and B 14 and 15, and 12-methoxyherbertenediol 16 from the
ether and ethyl acetate extracts of the Japanese liverwort Herbertus sakuraii.
The herbertane sesquiterpenes, mainly the phenolic herbertanes,[1,5]
have been shown to possess interesting biological properties, such as
Received in India April 30, 2007
Address correspondence to A. Srikrishna, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India. E-mail: ask@orgchem.iisc.ernet.in
4123

4124
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
Figure 1. Herbertane sesquiterpenes isolated from Herbertus species.
growth-inhibiting activity. Some of the phenolic herbertenes were found to be
strong inhibitors of the plant pathogenic fungi Botrytis cinerea, Rhizoctonia
solani, and Pythium debaryanum.[4] Presence of a sterically crowded 1-aryl-
1,2,2-trimethylcyclopentane carbon framework, the difficulty associated
with the construction of vicinal quaternary carbon atoms on a cyclopentane
ring and the significant biological properties associated with the phenolic her-
bertanes made herbertenoids interesting and challenging synthetic targets.
Prior to 1999, only 3 reports appeared in the literature on the synthesis of
phenolic herbertanes. However, during the past seven years, nearly 40
reports appeared in the literature on the synthesis of phenolic herbertanes,
making it a topic of contemporary interest.[6] We have developed a combi-
nation of Claisen rearrangement and ring-closing metathesis (RCM)
reactions[6b] for the synthesis of phenolic herbertenes. Herein we describe
the first total synthesis of 12-methoxyherbertenediol dimethyl ether and
12-homoherbertenediol.
Retrosynthetic analysis is depicted in Scheme 1. It was anticipated that
12-methoxyherbertenediol dimethyl ether 17 could be obtained from the
enone 18, containing the requisite two vicinal quaternary carbons, which in
turn could be obtained from the hydroxydiene 19 via an RCM reaction.[7]
The hydroxydiene 19 could be prepared from the aldehyde 20, which in
turn could be obtained from the acetophenone 21 via the Claisen rearrange-
ment of the cinnamyl alcohol 22.
Because synthesis of 2,3-dimethoxy-5-(methoxymethyl)acetophenone 21
is not reported in the literature, attention was first focused on the synthesis of
the acetophenone 21. Presence of two-ortho oriented oxygen substituents

(+)-12-Methoxyherbertenediol Dimethyl Ether
4125
Scheme 1.
prompted us to choose vanillin 23 as the appropriate starting material. An
aromatic Claisen rearrangement was contemplated for the introduction of
the side chain at the C-5 position of vanillin, as the aldehyde group could
easily be converted into a methoxymethyl group (Scheme 2). Thus, reaction
of vanillin 23 with allyl bromide and potassium carbonate in refluxing
acetone furnished the allyl ether 24 in quantitative yield. Reduction of the
aldehyde group in 24 with sodium borohydride in methanol gave the benzyl
alcohol 25, which on treatment with sodium hydride and methyl iodide in a
mixture of THF and DMF in the presence of tetrabutylammonium iodide
(TBAI) generated the methyl ether 26 in 87% yield (for two steps). Claisen
rearrangement of the allyl ether 26 by thermal activation to 1808C in a
sealed tube furnished the phenol 27 in 92% yield. Methanolic potassium
hydroxide–mediated isomerization of the terminal olefin in 27 furnished the
phenol 28, which on treatment with sodium hydroxide and dimethyl sulfate
generated the styrene 29 in 83% yield (for two steps). Ozonolysis of the
styrene 29 followed by reductive workup with dimethyl sulfide furnished
the aldehyde 30 in 84% yield. A two-step protocol was adopted for the con-
version of the aldehyde 30 into the acetophenone 21. Accordingly, reaction
of the aldehyde 30 with methylmagnesium iodide in ether at ice temperature
followed by oxidation of the resultant benzyl alcohol 31 with pyridinium
chlorochromate (PCC) and silica gel in methylene chloride at room tempera-
ture, which generated the acetophenone 21 in 96% yield, whose structure was
established from its spectral data.
Horner–Wadsworth–Emmons reaction of the acetophenone 21 with
triethyl phosphonoacetate and sodium hydride in refluxing THF furnished a
ꢀ15:1 E:Z mixture of the cinnamate 32, which on regioselective reduction
at low temperature (2508C) with lithium aluminium hydride (LAH) gave
an E,Z-mixture of the allyl alcohol 22 (Scheme 3). Next, attention was
focused on the creation of the first quaternary carbon atom, and Johnson’s
orthoester variant[8] of the Claisen rearrangement was employed. Thus,
thermal activation of the allyl alcohol 22 with triethyl orthoacetate in the
presence of a catalytic amount of propionic acid in a sealed tube at 1808C

4126
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
Scheme 2. (a) K2CO3, acetone, CH255CHCH2Br; (b) NaBH4, MeOH; (c) NaH, THF-
DMF, TBAI, MeI; (d) 1808C; (e) KOH, MeOH; (f) NaOH, Me2SO4; (g) O3, MeOH-
CH2Cl2; Me2S; (h) MeMgI, Et2O; (i) PCC, silica gel, CH2Cl2.
for 48 h generated the g,d-unsaturated ester 33 in 80% yield. Reduction of the
ester 33 with LAH in ether at 08C furnished the primary alcohol 34, which on
oxidation with PCC and silica gel furnished the aldehyde 20 in 87% yield (for
two steps). Grignard reaction of the aldehyde 20 with vinylmagnesium
bromide in dry THF at room temperature generated, as expected, a 1:1
epimeric mixture of the hydroxydiene 19 in 85% yield. Treatment of the
hydroxydiene 19 with 5 mol% of Grubbs’s first-generation catalyst
[PhCH55Ru(PCy3)2Cl2] in anhydrous methylene chloride at room tempera-
ture for 1 h furnished a 1:1 diastereomeric mixture of the cyclopentenol 35
in 86% yield, which on oxidation with PCC and anhydrous sodium acetate
furnished the cyclopentenone 36 in 97% yield. Presence of the molecular
ion peak at m/z 276 (C14H16O2) in the mass spectrum and in the IR
spectrum presence of a strong carbonyl absorption band at 1716 cm21 due
1
to cyclopentenone indicated the formation of the enone 36. In the H NMR
spectrum, the presence of two typical doublets at d 7.77 and 6.10 due to the
b and a protons, respectively, of a cyclopentenone, two singlets at 4.31 and
3.35 due to methoxymethyl group, an AB quartet at 2.65 and 2.53 due to
the diastereotopic methylene adjacent to the ketone, and a singlet at
1.54 ppm due to the tertiary methyl group established the structure of the
cyclopentenone 36. The 16-line 13C NMR spectrum with diagnostic quatern-
ary carbon resonance at d 208.7 due to the ketone carbon, two methines at
170.5 and 130.8 due to the b and a-olefinic carbons, respectively, of a cyclo-
pentenone, and a methylene at 50.9 ppm due to the carbon adjacent to the
ketone in addition to other resonances confirmed the structure of the cyclopen-
tenone 36. Reaction of the cyclopentenone 36 with sodium hydride and methyl

(+)-12-Methoxyherbertenediol Dimethyl Ether
4127
Scheme 3. (a) (EtO)2P(O)CH2CO2Et, NaH, THF; (b) LAH, Et2O; (c) MeC(OEt)3,
EtCO2H, D; (d) LAH, Et2O; (e) PCC, silica gel, CH2Cl2; (f) CH255CH-MgBr, THF;
(g) PhCH55Ru(PCy3)2Cl2, CH2Cl2; (h) PCC, NaOAc, CH2Cl2; (i) NaH, THF, DMF,
MeI; (j) H2, 10% Pd-C, EtOH; (k) NaBH4, MeOH; (l) NaH, imidazole, CS2, MeI;
(m) n-Bu3SnH, AIBN, C6H6; (n) MeMgI, xylene.
iodide in dry THF and DMF at room temperature generated the enone 18, in
85% yield. Hydrogenation of the enone 18 using 10% palladium over carbon
as the catalyst at one atmospheric pressure (balloon) of hydrogen in ethanol
for 2 h quantitatively furnished the cyclopentanone 37, whose structure was
established from its spectral data. As the cyclopentanone 37 was found to
be sensitive to acidic condition (due to the presence of benzylic methoxy
group), Barton’s radical deoxygenative strategy[9] was adopted for the
reductive deoxygenation of the ketone in 37. Thus, reaction of the cyclopen-
tanone 37 with sodium borohydride furnished a ꢀ2:1 diastereomeric mixture
of the alcohol 38. Treatment of the alcohol 38 with sodium hydride and
imidazole in THF followed by reaction of the resultant alkoxide with

4128
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
carbon disulfide and methyl iodide generated the dithiocarbonate 39. Reaction
of the dithiocarbonate 39 with tri-n-butyltin hydride and a catalytic amount of
azobisisobutyronitrile (AIBN) in refluxing benzene furnished 12-methoxyher-
bertenediol dimethyl ether 17, whose structure was established from its NMR
spectral data. Because the benzylic methoxy group was found to be sensitive
to acidic conditions, a Grignard reagent–mediated demethylation of the
aromatic methoxy groups was explored. However, treatment of the
trimethyl ether 17 with an excess of methylmagnesium iodide in refluxing
xylene furnished 12-homoherbertenediol 40 in 76% yield, whose structure
was established from its spectral data, in particular the presence of a quartet
at d 2.52 and a triplet at 1.18 ppm.
In conclusion, we have accomplished the first total synthesis of (+)-12-
methoxyherbertenediol dimethyl ether 17 and 12-homoherbertenediol 40. In
the present synthesis, a combination of Claisen rearrangement, RCM, and alky-
lation reactions were employed for the efficient generation of the requisite cyclo-
pentane containing two vicinal quaternary carbon atoms. The requisite starting
material, acetophenone 21, was prepared efficiently from vanillin in 9 steps
with an average yield of 93.5% for each step. The acetophenone 21 was then effi-
ciently converted into the target molecule 17 in 13 steps in 21% overall yield.
EXPERIMENTAL SECTION
IR spectra were recorded on a Jasco FTIR 410 spectrophotometer. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on a JNM
l-300 spectrometer. The chemical shifts (d ppm) and coupling constants
(Hz) are reported in the standard fashion with reference to either internal tet-
ramethylsilane (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 DEPT-135 spectra and is given in parentheses.
Low-resolution mass spectra were recorded using a Shimadzu QP-5050A
GCMS instrument using direct inlet mode. Relative intensities are given in
parentheses. High-resolution mass spectra were recorded on a Micromass
Q-TOF micromass spectrometer using electron spray ionization mode.
Hydrogenation reactions at one atmospheric pressure were carried out
using a balloon filled with hydrogen. Acme’s silica gel (100–200 mesh)
was used for column chromatography (approximately 15–20 g per 1 g of
the crude product). All small-scale dry reactions were carried out using
the standard syringe-septum technique.
4-Allyloxy-3-methoxybenzaldehyde (24)
A magnetically stirred suspension of vanillin 23 (2.5 g, 13.3 mmol),
anhydrous K2CO3 (4.59 g, 33.25 mmol), and allyl bromide (2.85 ml,

(+)-12-Methoxyherbertenediol Dimethyl Ether
4129
33.25 mmol) in acetone (5 ml) was refluxed for 5 h. The reaction mixture was
cooled to rt, and the solvent was evaporated under vacuum. Water (8 ml) was
added to the residue and extracted with ether (3 ꢀ 6 ml). Evaporation of the
solvent and purification of the residue on a silica-gel column using ethyl
acetate–hexane (1:4) as eluent furnished the allyl ether 24 (3.25 g, 100%)
1
as oil. IR (neat): nmax/cm21 2731, 1683, 1650, 1586, 1508, 1268. H NMR
(300 MHz, CDCl3 þ CCl4): d 9.80 (1H, s), 7.40–7.30 (2H, m), 6.91 (1H, d,
J 8.7 Hz), 6.06 (1H, ddt, J 17.4, 11.7 and 5.1 Hz), 5.43 (1H, dq, J 17.4 and
1.5 Hz), 5.32 (1H, dq, J 11.7 and 1.5 Hz), 4.66 (2H, dt, J 5.4 and 1.5 Hz),
3.92 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 189.8 (CH, CHO),
153.4 (C), 150.0 (C), 132.4 (CH), 130.3 (C), 126.2 (CH), 118.4 (CH2),
111.8 (CH2), 109.3 (CH), 69.5 (CH2), 55.7 (CH3). Mass: m/z 192 (Mþ,
89%), 151 (91), 149 (12), 109 (13), 105 (11), 95 (100). HRMS: m/z calcd.
for C11H12O3Na (M þ Na): 215.0684. Found: 215.0681.
4-Allyloxy-3-methoxybenzyl alcohol (25)
To a magnetically stirred solution of the aldehyde (2 g, 10.4 mmol) in
anhydrous methanol (3 ml) at 08C, NaBH4 (117 mg, 3.13 mmol) was added
in portions and stirred for 5 min. The solvent was then removed under
vacuum at rt. Water (5 ml) was added to the residue and extracted with
ether (3 ꢀ 5 ml). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate–hexane (1:3) as eluent furnished
the alcohol 25 (2.13 g, 95%) as oil. IR (neat): nmax/cm21 3253, 1591, 1514,
1
1139, 926, 853, 806. H NMR (300 MHz, CDCl3 þ CCl4): d 6.83 (1H, s),
6.75 (2H, s), 6.03 (1H, ddt, J 17.4, 10.5, 5.4 Hz), 5.37 (1H, dq, J 17.4 and
1.5 Hz), 5.24 (1H, d, J 10.5 and 1.5 Hz), 4.53 (2H, d, J 5.4 Hz), 4.50
(2H, s), 3.82 (3H, s), 2.17 (1H, brs). 13C NMR (75 MHz, CDCl3 þ CCl4): d
149.7 (C), 147.5 (C), 134.2 (C), 133.5 (CH), 119.2 (CH), 117.7 (CH2),
113.6 (CH), 111.0 (CH), 69.9 (CH2), 64.9 (CH2), 55.7 (CH3). Mass:
m/z 194 (Mþ, 68%), 153 (100), 121 (42), 105 (10), 97 (77), 95 (18), 94
(43). HRMS: m/z calcd. for C11H14O3Na (M þ Na): 217.0837. Found:
217.0835.
Allyl 2-Methoxy-4-(methoxymethyl)phenyl Ether (26)
A suspension of sodium hydride (210 mg, 60% dispersion in oil, 5.26 mmol)
in hexanes (2 ml) under nitrogen atmosphere was magnetically stirred for
10 min, and the solvent was syringed out. The oil-free sodium hydride was
then suspended in dry THF (2 ml). Anhydrous DMF (0.5 ml), methyl iodide
(0.38 ml. 6.18 mmol), tetra n-butylammonium iodide (0.05 g), and the
alcohol 25 (1 g, 5.15 mmol) in THF (3 ml) were added sequentially.
The reaction mixture was magnetically stirred for 12 h at rt. It was

4130
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
then quenched with water (5 ml) and extracted with ether (3 ꢀ 5 ml).
The combined ether extract was washed with brine and dried (Na2SO4). Evap-
oration of the solvent and purification of the residue on a silica-gel column
using methylene chloride–hexane (1:9) as eluent furnished the product 26
(986 mg, 92%) as oil. IR (neat): nmax/cm21 1592, 1514, 1262, 926, 854,
1
805. H NMR (300 MHz, CDCl3 þ CCl4): d 6.84 (1H, d, J 1.2 Hz), 6.79
(1H, d, J 7.8 Hz), 6.75 (1H, dd, J 7.8 and 1.2 Hz), 6.05 (1H, ddt, J 17.1,
10.2 and 5.4 Hz), 5.38 (1H, dq, J 17.1 and 1.5 Hz), 5.25 (1H, dq, J 10.2 and
1.5 Hz), 4.56 (2H, dt, J 5.4 and 1.5 Hz), 4.34 (2H, s), 3.87 (3H, s), 3.33
(3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 149.7 (C), 147.7 (C), 133.6
(CH), 131.2 (C), 120.1 (CH), 117.7 (CH2), 113.4 (CH), 111.5 (CH), 74.5
(CH2), 69.9 (CH2), 57.7 (CH3), 55.7 (CH3). HRMS: m/z calcd. for
C12H16O3Na (M þ Na): 231.0993. Found: 231.0993.
2-Allyl-6-methoxy-4-methoxymethylphenol (27)
Allyl ether 26 (750 mg, 3.61 mmol) was heated at 1808C in a sealed tube for
24 h. It was then cooled to rt. Purification of the residue on a silica-gel column
using ethyl acetate–hexane (3:17) as eluent furnished the phenol 27 (690 mg,
1
92%). IR (neat): nmax/cm21 3414, 1638, 1605, 1498, 1077, 911. H NMR
(300 MHz, CDCl3 þ CCl4): d 6.71 (1H, s), 6.64 (1H, s) 5.95 (1H, ddt, J
17.1, 9.9 and 6.3 Hz), 5.64 (1H, s), 5.05 (1H, dd, J 17.1 and 1.2 Hz), 5.01
(1H, dd, J 9.9 and 1.2 Hz), 4.31 (2H, s), 3.88 (3H, s), 3.37 (1H, d, J
6.6 Hz), 3.32 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 146.3 (C),
143.0 (C), 136.6 (CH), 129.2 (C), 125.4 (C), 122.0 (CH), 115.6 (CH2),
108.2 (CH), 74.8 (CH2), 57.6 (CH3), 55.9 (CH3), 33.9 (CH2). HRMS: m/z
calcd. for C11H13O2 (M-OMe): 177.0917. Found: 177.0912.
2-(Propen-1-yl)-6-methoxy-4-methoxymethylphenol (28)
A solution of the phenol 27 (300 mg, 1.44 mmol) in saturated methanolic
KOH (5 ml) was refluxed for 8 h. The reaction mixture was then cooled to
rt, acidified with 3 N HCl, and extracted with ether (3 ꢀ 4 ml). Evaporation
of the solvent and purification of the residue furnished the isomerized
product 28 (286 mg, 95%) as oil. IR (neat): nmax/cm21 3413, 1597, 1079,
1
970. H NMR (300 MHz, CDCl3 þ CCl4): d 6.88 (1H, s), 6.67 (1H, s), 6.62
(1H, d, J 15.9 Hz), 6.24 (1H, dq, J 15.9 and 6.3 Hz), 5.83 (1H, s), 4.32 (2H,
s), 3.86 (3H, s), 3.32 (3H, s), 1.89 (2H, d, J 6.3 Hz). 13C NMR (75 MHz,
CDCl3 þ CCl4): d 146.6 (C), 142.1 (C), 128.9 (C), 126.3 (CH), 125.3 (CH),
123.7 (C), 118.4 (CH), 108.1 (CH), 74.8 (CH2), 57.5 (CH3), 55.8 (CH3),
18.9 (CH3). HRMS: m/z calcd. for C11H13O2 (M-OMe): 177.0912. Found:
177.0917.

(+)-12-Methoxyherbertenediol Dimethyl Ether
4131
1,2-Dimethoxy-5-methoxymethyl-3-(1-propenyl)benzene (29)
To a cold (08C), magnetically stirred solution of the phenol 28 (256 mg,
1.23 mmol) in 3 M aqueous NaOH (3 ml), dimethyl sulfate (0.17 ml,
2.46 mmol) [washed with cold water and cold saturated aq. NaHCO3]
was added, and the reaction mixture was gently refluxed for 3 h. It was
cooled to rt and extracted with hexane (2 ꢀ 3 ml). The hexane layer was
washed with 40% aqueous NaOH solution (6 ml) and brine and dried
(Na2SO4). Evaporation of the solvent and purification of the residue over
a silica-gel column using hexane as eluent furnished the product 29
(240 mg, 88%). IR (neat): nmax/cm21 1580, 1147, 1101. 1H NMR
(300 MHz, CDCl3 þ CCl4): d 6.94 (1H, s), 6.73 (1H, s), 6.67 (1H, dd, J
15.6 and 1.5 Hz), 6.22 (1H, dq, J 15.6 and 6.6 Hz), 4.35 (2H, s), 3.86
(3H, s), 3.77 (3H, s), 3.36 (3H, s), 1.91 (3H, dd, J 6.6 and 1.5 Hz). 13C
NMR (75 MHz, CDCl3 þ CCl4): d 153.0 (C), 145.6 (C), 133.7 (C), 131.6
(C), 126.8 (CH), 125.4 (CH), 117.2 (CH), 109.9 (CH), 74.7 (CH2), 60.6
(CH3), 57.9 (CH3), 55.7 (CH3), 19.0 (CH3). HRMS: m/z calcd. for
C12H15O2 (M-OMe): 191.1068. Found: 191.1070.
2,3-Dimethoxy-5-methoxymethylbenzaldehyde (30)
Precooled dry ozone gas was passed through a cold (2708C) suspension of the
olefin 29 (2.2 g, 9.91 mmol) and NaHCO3 (50 mg) in 1:4 MeOH-CH2Cl2
(30 ml) for 25 min. Excess ozone was flushed off with oxygen. Evaporation
of the solvent under vacuum and purification of the residue on a silica-gel
column using ethyl acetate–hexane (1:4) as eluent furnished the aldehyde
30 (1.75 g, 84%). IR (neat): nmax/cm21 2753, 1687, 1606, 1586, 1147, 998.
1H NMR (300 MHz, CDCl3 þ CCl4): d 10.38 (1H, s), 7.29 (1H, s), 7.15
(1H, s), 4.40 (2H, s), 3.97 (3H, s), 3.93 (3H, s), 3.37 (3H, s). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 189.3 (CH), 153.2 (C), 152.2 (C), 134.4 (C),
129.3 (C), 118.0 (CH), 116.9 (CH), 73.9 (CH2), 62.1 (CH3), 58.1 (CH3),
56.0 (CH3). HRMS: m/z calcd. for C11H15O4 (M þ H): 211.0966. Found:
211.0961.
1-(2,3-Dimethoxy-5-methoxymethylphenyl)ethanol (31)
To a cold (08C), magnetically stirred solution of MeMgI [freshly prepared
from Mg (316 mg, 13 mmol) and MeI (1.01 ml, 16.2 mmol) in dry ether
(4 ml)], a solution of the aldehyde 30 (1.35 g, 6.5 mmol) in dry ether (4 ml)
was added over a period of 10 min and stirred at rt for 30 min. The reaction
mixture was poured into ice-cold aqueous NH4Cl solution (10 ml) and
extracted with ether (3 ꢀ 5 ml). The ether extract was washed with brine
and dried (Na2SO4). Evaporation of the solvent furnished the alcohol 31

4132
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
(1.46 g, 98%) as oil. IR (neat): nmax/cm21 3429, 1591, 1061. 1H NMR
(300 MHz, CDCl3 þ CCl4): d 6.89 (1H, s), 6.81 (1H, s), 5.08 (1H, q, J
6.6 Hz), 4.36 (2H, s), 3.87 (3H, s), 3.85 (3H, s), 3.37 (3H, s), 2.45 (1H,
brs), 1.46 (3H, d, J 6.6 Hz). 13C NMR (75 MHz, CDCl3 þ CCl4): d 152.5
(C), 145.5 (C), 138.9 (C), 134.2 (C), 117.3 (C), 110.7 (CH), 74.6 (CH2),
65.9 (CH), 60.7 (CH3), 58.1 (CH3), 55.7 (CH3), 24.2 (CH3). HRMS: m/z
calcd. for C12H18O4Na (M þ Na): 249.1098. Found: 249.1115.
2,3-Dimethoxy-5-methoxymethylacetophenone (21)
To a magnetically stirred suspension of PCC (3.55 g, 16.5 mmol) and silica
gel (3.5 g) in dry CH2Cl2 (3.5 ml), a solution of the alcohol 31 (1.48 g,
6.61 mmol) in dry CH2Cl2 (1 ml) was added and stirred vigorously for 2 h
at rt. The reaction mixture was then filtered through a small silica-gel
column, and the column was eluted with excess CH2Cl2. Evaporation of the
solvent furnished the acetophenone 21 (1.46 g, 98%) as oil. IR (neat): nmax
/
cm21 1680, 1605, 1583, 1060. H NMR (300 MHz, CDCl3 þ CCl4): d 7.07
(1H, s), 7.01 (1H, s), 4.32 (2H, s), 3.85 (3H, s), 3.84 (3H, s), 3.31 (3H, s),
2.55 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 199.0 (C), 153.0 (C),
148.0 (C), 134.0 (C), 132.9 (C), 119.7 (CH), 114.7 (CH), 73.8 (CH2), 60.9
(CH3), 57.8 (CH3), 55.8 (CH3), 31.0 (CH3). Mass: m/z 224 (Mþ, 99%), 209
(100), 193 (72), 179 (18), 161 (37). HRMS: m/z calcd. for C12H16O4Na
(M þ Na): 247.0942. Found: 247.0936.
1
Ethyl 3-(2,3-Dimethoxy-5-methoxymethylphenyl)but-2-enoate (32)
A suspension of sodium hydride (313 mg, 60% dispersion in oil, 7.81 mmol) in
hexanes under a nitrogen atmosphere was magnetically stirred for 10 min, and
the solvent was syringed out. The oil-free NaH was then suspended in dry THF
(3 ml) and cooled in an ice bath. Triethyl phosphonoacetate (1.77 ml,
8.92 mmol) was added dropwise, and the reaction mixture was stirred for
30 min at rt. A solution of the acetophenone 21 (500 mg, 2.23 mmol) in dry
THF (2 ml) was added dropwise to the reaction mixture and stirred for 8 h at
rt. The reaction was then quenched by careful addition of saturated aqueous
NH4Cl solution and extracted with ether (3 ꢀ 3 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 (1:9) as eluent furnished predominantly E-isomer of the
cinnamate 32 (656 mg, 100%). IR (neat): nmax/cm21 1718, 1637, 1584, 848.
1H NMR (300 MHz, CDCl3 þ CCl4): d 6.86 (1H, s), 6.66 (1H, s), 5.86 (1H,
q, J 1.2 Hz), 4.35 (2H, s), 4.18 (2H, q, J 7.2 Hz), 3.88 (3H, s), 3.76 (3H, s),
3.37 (3H, s), 2.49 (3H, d, J 1.2 Hz), 1.31 (3H, t, J 7.2 Hz). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 166.2 (C), 155.9 (C), 152.9 (C), 145.6 (C),

(+)-12-Methoxyherbertenediol Dimethyl Ether
4133
138.0 (C), 134.0 (C), 119.8 (CH), 119.4 (CH), 111.6 (CH), 74.3 (CH2), 60.9
(CH3), 59.5 (CH2), 58.1 (CH3), 55.8 (CH3), 20.1 (CH3), 14.5 (CH3). Mass:
m/z 294 (Mþ, 20%), 264 (16), 263 (100), 235 (81), 217 (16), 203 (27), 189
(11), 175 (31). HRMS: m/z calcd. for C16H22O5Na (M þ Na): 317.1365.
Found: 317.1366.
E 3-(2,3-Dimethoxy-5-methoxymethylphenyl)but-2-enol (22)
To a cold (2508C), magnetically stirred solution of the cinnamate 32
(800 mg, 2.72 mmol) in dry ether (6 ml), LAH (100 mg, 2.72 mmol) was
added and stirred for 1 h. Ethyl acetate (0.5 ml) was added to the reaction
mixture to consume the excess LAH. The reaction mixture was then
quenched with water (10 ml) and extracted with ether (3 ꢀ 5 ml). The
combined ether extract was washed with brine and dried (Na2SO4). Evapor-
ation of the solvent and purification of the residue on a silica-gel column
using ethyl acetate–hexane (1:3) as eluent furnished the alcohol 22
1
(600 mg, 87%). IR (neat): nmax/cm21 3426, 1653, 1584, 1008. H NMR
(300 MHz, CDCl3 þ CCl4): d 6.81 and 6.66 (2H, 2 ꢀ d, J 2.1 Hz), 5.67
(1H, t, J 6.9 Hz), 4.35 (2H, s), 4.29 (2H, d, J 6.9 Hz), 3.87 (3H, s), 3.75
(3H, s), 3.37 (3H, s), 2.03 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d
152.7 (C), 145.8 (C), 138.7 (C), 137.5 (C), 133.8 (C), 128.7 (CH), 120.8
(CH), 110.7 (CH), 74.5 (CH2), 60.6 (CH3), 59.5 (CH2), 58.1 (CH3), 55.8
(CH3), 17.6 (CH3). Mass: m/z 252 (Mþ, 63%), 221 (33), 205 (71), 191
(66), 189 (100), 177 (71), 185 (66), 161 (33), 151 (31). HRMS: m/z calcd.
for C14H20O4Na (M þ Na): 275.1259. Found: 275.1255.
Ethyl 3-(2,3-Dimethoxy-5-methoxymethylphenyl)-3-methylpent-4-
enoate (33)
A solution of the allyl alcohol 22 (670 mg, 2.38 mmol), triethyl orthoacetate
(2.5 ml, 11.9 mmol), and propionic acid (10 ml) was placed in a sealed tube
and heated to 1808C for 48 h in an oil bath. The reaction mixture was
cooled to rt; diluted with ether (5 ml); washed with 3N HCl (5 ml),
saturated aqueous NaHCO3 (5 ml), and brine; and dried (Na2SO4). Evapor-
ation of the solvent and purification of the residue on a silica-gel column
using ethyl acetate–hexane (1:20) as eluent furnished the pentenoate 33
1
(676 mg, 80%) as oil. IR (neat): nmax/cm21 1733, 1584, 1099, 914, 848. H
NMR (300 MHz, CDCl3 þ CCl4): d 6.81 (1H, d, J 1.8 Hz), 6.76 (1H, d, J
1.8 Hz), 6.28 (1H, dd, J 17.4 and 10.8 Hz), 5.04 (1H, d, J 10.8 Hz), 4.97
(1H, d, J 17.4 Hz), 4.34 (2H, s), 3.93 (2H, q, J 6.9 Hz), 3.85 (3H, s). 3.80
(3H, s), 3.35 (3H, s), 3.07 (1H, d, J 14.1 Hz), 2.83 (1H, d, J 14.1 Hz), 1.55
(3H, s), 1.06 (3H, t, J 6.9 Hz). 13C NMR (75 MHz, CDCl3 þ CCl4): d 171.3
(C), 153.0 (C), 147.3 (C), 146.5, (CH), 138.6 (C), 132.5 (C), 119.2 (CH),

4134
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
111.3 (CH2), 110.7 (CH), 74.8 (CH2), 60.0 (CH3), 59.5 (CH2), 57.9 (CH3),
55.6 (CH3), 44.1 (CH2), 42.8 (C), 25.6 (CH3), 14.1 (CH3). Mass: m/z 322
(Mþ, 38%), 280 (20), 235 (29), 219 (24), 204 (45), 203 (100), 202 (75),
189 (72), 177 (52). HRMS: m/z calcd. for C18H26O5Na (M þ Na):
345.1678. Found: 345.1689.
3-(2,3-Dimethoxy-5-methoxymethylphenyl)-3-methylpent-
4-en-1-ol (34)
To a cold (08C), magnetically stirred solution of the pentenoate 33 (560 mg,
1.88 mmol) in dry ether (3 ml), LAH (70 mg, 1.88 mmol) was added. The
reaction mixture was stirred at the same temperature for 30 min. Ethyl
acetate (0.2 ml) was added to the reaction mixture to consume the excess
LAH. The reaction mixture was then quenched with water (10 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 on a silica-gel column using ethyl acetate–hexane (1:3) as
eluent furnished the alcohol 34 (480 mg, 99%). IR (neat): nmax/cm21 3421,
1
1583, 1007. H NMR (300 MHz, CDCl3 þ CCl4): d 6.79 (1H, s), 6.73 (1H,
s), 6.17 (1H, dd, J 17.4 and 10.8 Hz), 5.02 (1H, d, J 10.8 Hz), 4.97 (1H, d,
J 17.4 Hz), 4.33 (2H, s), 3.84 (3H, s), 3.77 (3H, s), 3.60–3.30 (2H, m), 3.36
(3H, s), 2.45–2.30 (1H, m), 2.20–1.95 (2H, m), 1.44 (3H, s). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 153.2 (C), 147.7 (CH), 147.5 (C), 139.4 (C),
132.7 (C), 119.1 (CH), 110.8 (CH2), 110.6 (CH), 74.9 (CH2), 60.0 (CH2),
58.0 (CH3), 55.6 (CH3), 43.0 (C), 42.1 (CH2), 25.9 (CH3). Mass: m/z 280
(Mþ, 46%), 254 (15), 235 (18), 217 (21), 205 (27), 204 (45), 203 (100),
191 (41), 189 (45), 175 (26). HRMS: m/z calcd. for C16H24O4Na (M þ Na):
303.1572. Found: 303.1574.
3-(2,3-Dimethoxy-5-methoxymethylphenyl)-3-methylpent-
4-enal (20)
To a magnetically stirred suspension of PCC (753 mg, 3.42 mmol) and
anhydrous NaOAc (284 mg, 3.42 mmol) in anhydrous CH2Cl2 (3 ml), a
solution of the alcohol 34 (480 mg, 1.71 mmol) in CH2Cl2 (1 ml) was added
and stirred at rt for 4 h. The reaction mixture was then filtered through a
small silica-gel column, and the column was eluted with excess CH2Cl2.
Evaporation of the solvent furnished the aldehyde 20 (425 mg, 89%) as oil.
IR (neat): nmax/cm21 2735, 1063, 1006, 916, 850. 1H NMR (300 MHz,
CDCl3 þ CCl4): d 9.46 (1H, brs), 6.84 (1H, s), 6.77 (1H, s), 6.20 (1H, dd, J
17.4 and 10.5 Hz), 5.12 (1H, d, J 10.5 Hz), 5.02 (1H, d, J 17.4 Hz), 4.35
(2H, s), 3.87 (3H, s), 3.81 (3H, s), 3.38 (3H, s), 3.12 (1H, d, J 15.3 Hz),
2.81 (1H, d, J 15.3 Hz), 1.54 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4):

(+)-12-Methoxyherbertenediol Dimethyl Ether
4135
d 202.4 (CH), 153.3 (C), 147.2 (C), 146.1 (CH), 137.8 (C), 133.0 (C), 118.8
(CH), 112.0 (CH2), 111.0 (CH), 74.7 (CH2), 60.1 (CH3), 58.1 (CH3), 55.7
(CH3), 52.1 (CH2), 42.2 (C), 26.3 (CH3). HRMS: m/z calcd. for
C16H22O4Na (M þ Na): 301.1416. Found: 301.1429.
5-(2,3-Dimethoxy-5-methoxymethylphenyl)-5-methylhepta-1,6-
dien-3-ol (19)
To a cold (08C), magnetically stirred solution of the aldehyde 20 (340 mg,
1.22 mmol) in THF (4 ml), a solution of vinylmagnesium bromide
[prepared from Mg (73 mg, 3.05 mmol) and vinyl bromide (0.26 ml,
3.66 mmol) in THF (6 ml)] was added dropwise and stirred at 08C for
5 min. The reaction mixture was then quenched with cold saturated aqueous
NH4Cl (10 ml) and extracted with ether (2 ꢀ 4 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 (1:4) as eluent furnished a ꢁ 1:1 diastereomeric mixture of
the alcohol 19 (318 mg, 85%) as oil. IR (neat): nmax/cm21 3431, 1636,
1
1584, 916, 848. H NMR (300 MHz, CDCl3 þ CCl4): d 6.80 (2H, brs), 6.27
(1H, dd, J 17.4 and 10.5 Hz), 5.90–5.70 (1H, m, H-2), 5.70–4.85 (4H, m),
4.34 (2H, s), 4.04 and 3.95 (1H, 2 ꢀ brs), 3.84 (3H, s), 3.80 and 3.77 (3H,
s), 3.36 (3H, s), 2.40–2.20 (1H, m), 2.05–1.90 (1H, m), 1.75 (1H, br s),
1.54 and 1.49 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 153.1 (C),
148.4 and 147.9 (CH), 147.5 (C), 142.2 and 142.1 (CH), 139.4 (C), 132.8
and 132.5 (C), 119.4 and 119.1 (CH), 113.2 and 112.9 (CH2), 110.8 (CH2),
110.7 (CH), 74.81 and 74.75 (CH2), 70.5 (CH), 60.0 (CH3), 57.9 (CH3),
55.6 (CH3), 46.7 and 46.2 (CH2), 43.6 and 43.4 (C), 26.3 (CH3). Mass: m/z
306 (Mþ, 7%), 236 (61), 203 (57), 191 (84), 189 (42), 173 (43), 151 (100).
HRMS: m/z calcd. for C18H26O4Na (M þ Na): 329.1729. Found: 329.1717.
4-(2,3-Dimethoxy-5-methoxymethylphenyl)-4-methylcyclopent-
2-en-1-ol (35)
To a magnetically stirred solution of a 1:1 diastereomeric mixture of the
hydroxydiene 19 (230 mg, 0.75 mmol) in anhydrous CH2Cl2 (50 ml), a
solution of Grubbs’ first generation catalyst (31 mg, 5 mol%) in anhydrous
CH2Cl2 (20 ml) was added. The reaction mixture was stirred at rt for 1 h.
Evaporation of the solvent under reduced pressure and purification of the
residue on a silica-gel column using ethyl acetate–hexane (1:10–1:5) as
eluent furnished a 1:1 diastereomeric mixture of the cyclopentenol 35
(180 mg, 86%) as oil. IR (neat): nmax/cm21 3407, 1584, 1143, 1060, 847.
1H NMR (300 MHz, CDCl3 þ CCl4): d 6.79 and 6.77 (1H, s), 6.75 and 6.66
(1H, s), 6.22 (d, J 6 Hz) and 6.12 (d, J 5.1 Hz) [1H], 5.90–5.80 (1H, m),

4136
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
4.90–4.75 (1H, m), 4.34 and 4.32 (2H, s), 3.86 (3H, s) and 3.84 and 3.82 (3H,
s), 3.38 and 3.37 (3H, s), 2.65–2.50 (1H, m), 2.05–1.90 (2H, m), 1.53 and
1.41 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 153.2 (C), 147.0 and
146.8 (C), 142.8 and 142.5 (CH), 141.8 and 141.7 (C), 132.9 and 132.6 (C),
131.6 and 131.5 (CH), 118.0 and 117.9 (CH), 110.34 and 110.29 (CH), 77.3
and 77.1 (CH), 74.8 (CH2), 60.4 and 60.2 (CH3), 58.0 and 58.0 (CH3), 55.6
(CH3), 51.8 and 50.5 (C), 50.3 and 49.3 (CH2), 30.4 and 29.0 (CH3). Mass:
m/z 308 (Mþ, 16%), 306 (9), 222 (7), 205 (27), 191 (22), 175 (16). HRMS:
m/z calcd. for C16H22O4Na (M þ Na): 301.1416. Found: 301.1414.
4-(2,3-Dimethoxy-5-methoxymethylphenyl)-4-methylcyclopent-
2-enone (36)
To a magnetically stirred suspension of PCC (350 mg, 1.62 mmol) and
anhydrous NaOAc (161 mg, 1.94 mmol) in anhydrous CH2Cl2 (3 ml), the
allyl alcohol 35 (180 mg, 0.647 mmol) in CH2Cl2 (1 ml) was added and
stirred at rt for 6 h. The reaction mixture was then filtered through a small
silica-gel column, and the column was eluted with excess CH2Cl2. Evapor-
ation of the solvent furnished the enone 36 (175 mg, 97%) as oil. IR (neat):
1
nmax/cm21 1716, 1585, 1056, 1006. H NMR (300 MHz, CDCl3 þ CCl4): d
7.77 (1H, d, J 5.4 Hz), 6.78 (1H, s), 6.66 (1H, s), 6.10 (1H, d, J 5.4 Hz),
4.31 (2H, s), 3.83 (3H, s), 3.76 (3H, s), 3.35 (3H, s), 2.65 and 2.53 (2H,
2 ꢀ d, J 18.6 Hz), 1.54 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d
208.7 (C), 170.4 (CH), 153.2 (C), 146.9 (C), 138.2 (C), 133.2 (C), 130.8
(CH), 117.9 (CH), 111.0 (CH), 74.6 (CH2), 60.3 (CH3), 58.2 (CH3), 55.7
(CH3), 50.9 (CH2), 47.3 (C), 28.3 (CH3). Mass: m/z 276 (Mþ, 100%), 245
(40), 229 (39). HRMS: m/z calcd. for C16H20O4Na (M þ Na): 299.1259.
Found: 299.1247.
4-(2,3-Dimethoxy-5-methoxymethylphenyl)-4,5,5-trimethylcyclopent-
2-enone (18)
A suspension of sodium hydride (149 mg, 60% dispersion in oil, 3.72 mmol)
in hexanes (1 ml) under nitrogen atmosphere was magnetically stirred for
10 min, and the solvent was syringed out. The oil-free sodium hydride was
then suspended in dry THF (1.0 ml). Anhydrous DMF (0.1 ml), methyl
iodide (0.39 ml, 6.2 mmol), and the enone 36 (170 mg, 0.62 mmol) were
added sequentially and magnetically stirred for 12 h at rt. It was then
quenched with water (4 ml) and extracted with ether (3 ꢀ 4 ml). The
combined ether extract was washed with brine and dried (Na2SO4). Evapor-
ation of the solvent and purification of the residue on a silica-gel column
using ethyl acetate–hexane (1:5) as eluent furnished the enone 18 (160 mg,
1
85%) as oil. IR (neat): nmax/cm21 1709, 1006, 840. H NMR (300 MHz,

(+)-12-Methoxyherbertenediol Dimethyl Ether
4137
CDCl3 þ CCl4): d 7.89 (1H, d, J 5.4 Hz), 6.79 (1H, s), 6.59 (1H, s), 6.06 (1H,
d, J 5.4 Hz), 4.34 (2H, s), 3.87 (3H, s), 3.83 (3H, s), 3.36 (3H, s), 1.48 (3H, s),
1.23 (3H, s), 0.64 (3H, s). 13C NMR (75 MHz, CDCl3 þ CCl4): d 213.5 (C),
170.4 (CH), 153.1 (C), 147.1 (C), 136.3 (C), 133.2 (C), 119.5 (CH), 110.6
(CH), 74.6 (CH2), 60.2 (CH3), 58.0 (CH3), 55.6 (CH3), 54.7 (C), 50.8 (C),
26.2 (CH3), 19.9 (CH3). Mass: m/z 304 (Mþ, 52%), 289 (100), 259 (100),
273 (5), 229 (8). HRMS: m/z calcd. for C18H24O4Na (M þ Na): 327.1572.
Found: 327.1583.
4-(2,3-Dimethoxy-5-methoxymethylphenyl)-2,3,3-trimethylcyclo-
pentanone (37)
Activated 10% Pd-C (100 mg) was added to a suspension of the enone 18
(140 mg, 0.46 mmol) and Na2CO3 (100 mg) in ethanol (1 ml). The reaction
mixture was stirred for 2 h at rt in an atmosphere of hydrogen created by eva-
cuative replacement of air (balloon). The catalyst was then filtered using a
small silica-gel column. Evaporation of the solvent furnished the saturated
ketone 37 (141 mg, 100%) as oil. IR (neat): nmax/cm21 1737, 1097, 847.
1H NMR (300 MHz, CDCl3 þ CCl4): d 6.88 (1H, s), 6.80 (1H, s), 4.36 (2H,
s), 3.87 (3H, s), 3.81 (3H, s), 3.38 (3H, s), 2.71–2.63 (1H, m), 2.50–2.35
(2H, m), 2.25–2.00 (1H, m), 1.35 (3H, s), 1.25 (3H, s), 0.72 (3H, s). 13C
NMR (75 MHz, CDCl3 þ CCl4): d 221.6 (C), 153.1 (C), 147.9 (C), 138.2
(C), 132.6 (C), 119.4 (CH), 110.2 (CH), 74.8 (CH2), 60.0 (CH3), 57.9
(CH3), 55.5 (CH3), 53.3 (C), 49.5 (C), 33.9 (CH2), 31.8 (CH2), 24.3 (CH3),
22.1 (CH3), 20.3 (CH3). Mass: m/z 306 (Mþ, 46%), 274 (20), 259 (25), 243
(10), 231 (10), 215 (20), 205 (100), 189 (25), 173 (48). HRMS: m/z calcd.
for C17H23O3 (M-OMe): 275.1648. Found: 275.1652.
3-(2,3-Dimethoxy-5-methoxymethylphenyl)-2,2,3-trimethylcyclo-
pentanol (38)
To an ice-cold magnetically stirred solution of the ketone 37 (110 mg,
0.131 mmol) in dry methanol (1 ml), NaBH4 (10 mg, 2.61 mmol) was added
and stirred for 5 min. The solvent was evaporated under reduced pressure.
Water (3 ml) followed by 3 N aqueous HCl were added to the reaction mixture
(4 ml) and extracted with ether (3 ꢀ 3 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
(1:19–1:10) as eluent furnished a ꢁ 2:1 epimeric mixture of the alcohol 38
1
(35 mg, 88%) as oil. IR (neat): nmax/cm21 3434, 1580, 1060, 1009, 846. H
NMR (300 MHz, CDCl3 þ CCl4): d 6.88 and 6.75 (2H, brs), 4.35 (2H, brs),
3.98 (dd, J 8.4 and 6.9 Hz) and 3.71 (t, J 7.5 Hz) [1H], 3.85 (3H, s), 3.78 (3H,
s), 3.36 (3H, s), 2.77–2.67 and 2.45–2.35 (1H, m), 2.26–2.14 (1H, m),

4138
A. Srikrishna, S. R. Kumar, and P. C. Ravikumar
1.85–1.50 (3H, m), 1.48 and 1.33 (3H, s), 1.13 and 1.02 (3H, s), 0.64 (3H, s). 13
C
NMR (75 MHz, CDCl3 þ CCl4): d 153.5 and 153.3 (C), 148.0 and 148.2 (C),
140.0 and 139.9 (C), 120.5 and 120.4 (CH), 110.0 and 109.9 (CH), 81.0 and
80.8 (CH), 75.0 (CH2), 60.3 (CH3), 57.9 (CH3), 55.6 (CH3), 51.0 and 50.9 (C),
47.9 and 47.8 (C), 36.8 and 35.0 (CH2), 31.3 and 30.0 (CH2), 25.4 and 25.2
(CH3), 24.3 and 23.0 (CH3), 18.8 and 18.4 (CH3). Mass: m/z 278 (Mþ, 75%),
263 (55), 231 (100), 215 (17), 201 (35), 191 (24), 172 (68). HRMS: m/z calcd.
for C18H28O4Na (M þ Na): 331.1885. Found: 331.1878.
1-(2,3-Dimethoxy-5-methoxymethylphenyl)-1,2,2-trimethylcyclopentyl
Methyl Dithiocarbonate (39)
To a magnetically stirred suspension of NaH (43 mg, 60% dispersion in oil,
1.07 mmol) in dry THF (1 ml), a solution of the alcohol 38 (33 mg,
0.107 mmol) in dry THF (0.5 ml) was added followed by a catalytic amount
of imidazole. The reaction mixture was heated to 608C for 15 min. It was
cooled to rt; CS2 (0.19 ml, 3.21 mmol) was added and refluxed for 15 min.
It was recooled to rt; MeI (0.2 ml, 3.21 mmol) was added and refluxed for
4 h. It was then cooled to rt, diluted with water (2 ml), and extracted with
ether (3 ꢀ 2 ml). The combined organic layer was washed with brine and
dried (Na2SO4). Evaporation of the solvent and rapid purification of the
residue on a silica-gel column using CH2Cl2–hexane (1:10) as eluent
furnished the dithiocarbonate 39 (33 mg, 79%) as a yellow oil, which was
found to be unstable on standing. IR (neat): nmax/cm21 1581, 1236, 1057,
1
847. H NMR (300 MHz, CDCl3 þ CCl4): d 6.83 and 6.78 (1H, s), 6.75
(1H, s), 5.51 (dd, J 7.5 and 5.4 Hz) and 5.69 (dd, J 7.8 and 5.4 Hz) [1H],
4.33 (2H, s) 3.84 and 3.85 (3H, s), 3.78 and 3.77 (3H, s), 3.33 and 3.34
(3H, s), 2.67–2.43 (2H, m), 2.53 and 2.50 (3H, s), 2.00–1.80 (2H, m), 1.51
and 1.40 (3H, s), 1.16 and 1.19 (3H, s), 0.73 and 0.78 (3H, s). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 215.3 and 214.9 (C), 153.5 and 148.5 (C),
138.9 and 138.6 (C), 132.4 and 132.3 (C), 120.3 and 120.2 (CH), 110.3 and
110.2 (CH), 93.0 and 92.7 (CH), 75.0 (CH2), 60.3 and 60.2 (CH3), 57.9
(CH3), 55.7 (CH3), 51.2 and 51.0 (C), 49.0 and 48.4 (C), 36.8 and 35.4
(CH2), 28.5 and 26.8 (CH2), 25.1 and 24.9 (CH3), 24.7 and 23.2 (CH3),
20.7 and 19.9 (CH3), 18.9 (CH3).
5-Methoxymethyl-3-(1,2,2-trimethylcyclopentyl)catechol Dimethyl
Ether (12-Methoxyherbertenediol Dimethyl Ether 17)
n
A solution of the dithiocarbonate 39 (33 mg, 0.08 mmol), Bu3SnH (0.05 ml,
0.19 mmol), and a catalytic amount of AIBN (5 mg) in dry benzene (1 ml) was
refluxed for 3 h. The reaction mixture was cooled; diluted with ether (2 ml);
washed successively with 1% aq NH4OH, water, and brine; and dried

(+)-12-Methoxyherbertenediol Dimethyl Ether
4139
(Na2SO4). Evaporation of the solvent and purification of the residue on a silica-gel
column using hexane as eluent furnished 12-methoxyherbertenediol dimethyl
ether 17 (20 mg, 82%) as a colorless oil. IR (neat): nmax/cm21 1581, 1143,
1009. 1H NMR (300 MHz, CDCl3 þ CCl4): d 6.89 (1H, d, J 1.8 Hz), 6.80 (1H,
d, J 1.8 Hz), 4.38 (2H, s), 3.86 (3H, s), 3.79 (3H, s), 3.38 (3H, s), 2.70–2.55
(1H, m), 1.90–1.20 (5H, m), 1.37 (3H, s), 1.13 (3H, s), 0.69 (3H, s). 13C NMR
(75 MHz, CDCl3 þ CCl4): d 153.4 (C), 148.6 (C), 140.2 (C), 131.9 (C), 120.7
(CH), 109.8 (CH), 75.2 (CH2), 60.3 (CH3), 57.9 (CH3), 55.7 (CH3), 51.7 (C),
45.2 (C), 41.1 (CH2), 39.2 (CH2), 27.1 (CH3), 25.5 (CH3), 24.3 (CH3), 20.4
(CH2). HRMS: m/z calcd. for C17H25O2 (M-OMe): 261.1848. Found: 261.1852.
5-Ethyl-3-(1,2,2-trimethylcyclopentyl)catechol
(12-homoherbertenediol 40)
Methylmagnesium iodide in ether (5 ml) was prepared using Mg (50 mg,
2.06 mmol) and CH3I (0.16 ml, 2.5 mmol). Solvent was evaporated under
vacuum. To the solid MeMgI, a solution of the dimethyl ether 17 (7 mg,
0.03 mmol) in dry xylene (2 ml) was added and refluxed for 8 h. It was then
cooled to rt, added to a cold saturated aq. NH4Cl solution (3 ml), and
extracted with ether (2 ꢀ 2 ml). Evaporation of the solvent and purification
of the residue on a silica-gel column using ethyl acetate–hexane (1:20) as
eluent furnished 12-homoherbertenediol 40 (5 mg, 76%). IR (neat): nmax
/
cm21 3517, 1597, 951, 854. H NMR (300 MHz, CDCl3 þ CCl4): d 6.70
(1H, d, J 1.8 Hz), 6.58 (1H, d, J 1.8 Hz), 5.36 (1H, brs), 5.04 (1H, brs),
2.70–2.55 (1H, m), 2.52 (2H, q, J 7.5 Hz), 1.85–1.50 (5H, m), 1.42 (3H,
s), 1.18 (3H, s), 1.18 (3H, t, J 7.5 Hz), 0.76 (3H, s). 13C NMR (75 MHz,
CDCl3 þ CCl4): d 143.4 (C), 141.1 (C), 134.9 (C), 133.4 (C), 120.8 (CH),
112.1 (CH), 51.2 (C), 44.9 (C), 40.9 (CH2), 39.2 (CH2), 28.5 (CH2), 26.8
(CH3), 25.4 (CH3), 22.9 (CH3), 20.3 (CH2), 15.8 (CH3). HRMS: m/z calcd.
for C16H24O2Na (M þ Na): 271.1674. Found: 271.1686.
1
ACKNOWLEDGMENTS
We thank G. Nagaraju for checking the reproducibility of some of the
reactions. Two of us (S. R. K. and P. C. R.) thank Council of Scientific and
industrial Research (CSIR), New Delhi, for the award of research fellowships.
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