An efficient synthesis of (±)-β-herbertenol by a 1,3-cyclopentadione annelation strategy

Article abstract of DOI:10.1016/S0040-4020(03)00236-9

A simple and efficient synthesis of sesquiterpene (±)-β-herebertenol is described. The formation of cyclopentadione onto the aromatic moiety is the key feature of this protocol.

Full text of DOI:10.1016/S0040-4020(03)00236-9

Tetrahedron 59 (2003) 2737–2741
An efficient synthesis of (6)-b-herbertenol
by a 1,3-cyclopentadione annelation strategy
*
Subhash P. Chavan, Rajendra K. Kharul, Ramesh R. Kale and Dushant A. Khobragade
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 4 July 2002; revised 14 January 2003; accepted 6 February 2003
Abstract—A simple and efficient synthesis of sesquiterpene (^)-b-herebertenol is described. The formation of cyclopentadione onto the
aromatic moiety is the key feature of this protocol. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
cuparene-type sesquiterpenoid, viz. (^)-a-cuparenone,7 we
attempted the synthesis of (^)-b-herbertenol 5.
Numerous herbertene type sesquiterpenoids, an expanding
group of natural products possessing a 3-methyl-1-(1,2,2-
trimethylcyclopentyl) cyclohexane skeleton 1 have been
isolated from Herbertous species and other liverworts.1,2
Some of these compounds, particularly, those with an
oxygenated aromatic six-membered ring [e.g. (2)-a-
herbertenol,3 (2)-herbertenediol4 and (2)-b-herbertenol5]
show a wide spectrum of biological properties which
include potent antifungal,1a,b neurotrophic,3 and anti-lipid
peroxidation4 activities. Some complicated dimeric phenols,
belonging to this class are also biologically active.
2. Results and discussion
The central idea of our synthetic route is to construct the
cyclopenta-1,3-dione system 9 where the tertiary methyl
group would be introduced at an early stage in the synthesis
and then to elaborate it to b-herbertenol. To investigate this
idea, cyclopenta-1,3-dione 9 was prepared by annelation of
1,3-dioxalane 7 and 1,2-disilyloxycyclobutene 8.8 Cyclo-
penta-1,3-dione 9 was subjected to Wittig reaction and
mono-olefination was explited. Under optimized reaction
conditions, cyclopentadione 9 was added at room tempera-
ture to the in situ generated ylide (1 equiv. prepared from
Wittig salt PPhþ3 MeI2 and Kþtert. BuO2 in refluxing
benzene for 1 h) stirred for 15 min, followed by addition of
Wittig salt (1 eqiuv.) and the base (1 equiv.) and refluxing it
for 15 min followed by further addition of Wittig salt
(0.25 equiv) and the base (0.25 equiv.) and further refluxing
the reaction mixture for 15 min to ensure the completion of
the reaction. Thus the exomethylene derivative 10 was
obtained in 73% yield as a major product along with minor
amounts (3%) of the di-exomethylene compound. If the
Wittig salt (in all 2.25 equiv.) and the base (in all
2.25 equiv.) were mixed in a single portion and all the
ylide was generated at the start, cyclopentadione 9 furnished
the di-exomethylene compound as the major product.
The total synthesis of herbertene-type 1 as well as cuparene-
type 2 sesquiterpenoids have attracted attention due to the
difficulty associated with the construction of the vicinal
quaternary carbons in the cyclopentane ring. A literature
survey indicates that, even though several synthetic
strategies are reported towards (^)-herbertene 6,5b (^)-a-
herbertenol 3,5a,e,6 (^)-herbertenediol 45d and their asym-
metric syntheses, only one synthetic strategy is reported
towards (^)-b-herbertenol 5.6
The exomethylene compound 10 was reduced with NaBH4
in ethanol at room temperature to furnish the secondary
alcohol which was subjected to hydroboration9 with BMS
complex followed by oxidative work up with alkaline H2O2
to furnish diol 11. Diol 11 thus obtained was protected
regioselectively as a pivaloate ester10 followed by its
conversion to xanthate derivative 1211 by treating it with
NaH/CS2 and methyl iodide. The xanthate derivative 12,
In continuation of our interest towards the total synthesis of
Keywords: (^)-b-herebertenol; Wittig reaction; reduction; annelation;
xanthates.
*
Corresponding author. Tel./fax: þ91-20-5893614;
e-mail: spchavan@dalton.ncl.res.in
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00236-9

2738
S. P. Chavan et al. / Tetrahedron 59 (2003) 2737–2741
THF was freshly distilled from sodium benzophenone ketyl
prior to use. All the reactions were monitored by TLC on
0.25 mm Merck Kieselgel TLC plate using ethanolic
p-anisaldehyde solution with heating for visualization.
Chromatography were performed on silica gel (60–120
mesh).
4.1.1. 2-(4-Methoxy-3-methylphenyl)-2-methyl cyclopen-
tane-1,3-dione [9]. In an inert and moisture free atmos-
phere, BF3·Et2O (55.56 g, 49 mL, 0.39 mol) was added
dropwise to the solution of 1,3-dioxolane 7 (8.13 g,
0.039 mol) and trimethylsilyloxy cyclobutene 8 (27 g,
0.12 mol) in dry dichloromethane (85 mL) at 2788C. The
reaction mixture was stirred at 2788C for 8 h, then slowly
brought to room temperature over 1 h and stirred overnight.
The reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was diluted with ethyl
acetate (100 mL) and quenched by addition of saturated
NaHCO3 (80 mL) in portions. The organic layer was
washed with water (2£50 mL), brine (50 mL), dried over
anhydrous sodium sulphate, filtered and the solvent
removed under reduced pressure to furnish cyclopentadione
9. The product was purified by crystallization from hexane–
ethyl acetate 90:10.
Scheme 1. Reagents and conditions: (a) BF3·Et2O, 2788C, 68%. (b) PPh3þ-
MeI2 (2.25 equiv.), KþtertBuO2 (2.25 equiv.) C6H6, reflux–room tem-
perature, 72%. (c) (i) NaBH4 (1.5 equiv.), EtOH, room temperature,
30 min, 98%; (ii) BMS (2.5 equiv.), THF, 08C, 2 h then at room
temperature 24 h, then H2O2, HO2, 08C–room temperature, 1 h, 71%.
(d) (i) (CH3)3CCOCl (1.5 equiv.), Et3N (2.5 equiv.), DCM, 08C–room
temperature, 84%; (ii) NaH (1.5 equiv.) THF:CS2, 4:1, room temperature,
3 h, then MeI (3 equiv.) room temperature 16 h, 86%. (e) TBTH (5 equiv.),
AIBN, toluene, reflux, 1.5 h, 83%. (f) (i) LiAlH4 (2 equiv.), THF, room
temperature 92%; (ii) PCC (1.5 equiv.), CH2Cl2, 08C–room temperature,
1 h, 86%. (g) NaH (1.2 equiv.), DME, 08C, 30 min, MeI (1.6 equiv.), 08C,
3 h, then at room temperature 16 h, 65%. (h) H2NNH2·H2O (7 equiv.),
NaOH (9 equiv.), TEG, 1958C, 7 h, 52%. (i) BBr3 (5 equiv.), CH2Cl2,
2788C–room temperature, 1 h 81%.
thus obtained was subjected to deoxygenation11a,12 with
tri-n-butyltinhydride in refluxing toluene with AIBN as an
initiator to furnish the compound 13. Compound 13 thus
obtained was reductively cleaved with LiAlH4 in anhydrous
THF at room temperature to furnish primary alcohol which
was then oxidized with PCC in dichloromethane to furnish
compound 14. Aldehyde 14 was alkylated13 with CH3I/NaH
to furnish 15. The aldehyde functionality of the aldehyde 15
was reduced to a methyl group by Wolff–Kishner reduction
Yield 6.16 g (68%). White solid. Mp 71–728C. IR (CHCl3)
nmax (cm21): 2975, 1765, 1725, 1505, 1440, 1301, 1254,
1217, 1145, 1030, 815, 757, 668. 1H NMR (CDCl3,
200 MHz) d: 1.39 (s, 3H), 2.18 (s, 3H), 2.61–2.98 (m,
4H), 3.81 (s, 3H), 6.82 (d, 1H, J¼8.5 Hz), 6.94–6.99 (m,
2H). 13C NMR (CDCl3, 50 MHz) d: 15.07 (q), 19.46 (q),
35.01 (t, 2£–CH2), 110.51 (d), 124.81 (d), 127.82 (s),
157.45 (s), 212.85 (s). Mass (m/z): 232 (Mþ, 82), 189 (8),
176 (34), 162 (36), 148 (100), 133 (62), 115 (22), 103 (24),
91 (20), 77 (48), 55 (16). HRMS: Mþ, found 232.1094.
C14H16O3 requires 232.1099.
14
in 52% yield. Compound 16 was demethylated with BBr3
in dichloromethane at 2788C to furnish (^)-b-herbertenol
5. (^)-b-Herbertenol 5 had physical and spectral properties
identical with the ones reported in the literature (Scheme
1).1a,6
4.1.2. 2-[4-Methoxy-3-methylphenyl)-2-methyl-3-methyl-
ene cyclopentenone [10]. The exomethylene compound 10
was obtained by the Wittig reaction of corresponding
cyclopentadione 9. Thus the ylide was generated from
Wittig salt PPh3CH3I (6.97 g, 17.24 mmol) and t-BuOK
(1.93 g, 17.24 mmol) in refluxing benzene (35 mL) for 1 h.
It was cooled to room temperature and cyclopentadione
9 (4 g, 17.24 mmol) in dry benzene (15 mL) was added
dropwise over 10 min. The reaction mixture was stirred at
room temperature for 15 min. Again Wittig salt PPh%3 CH3I*
(6.97 g, 17.24 mmol) and tert-BuOK (1.93 g, 17.24 mmol)
were added and refluxed for 30 min. The reaction was
monitored by TLC. To ensure the completion of the
reaction, Wittig salt PPh%3 CH3I* (1.75 g, 4.32 mmol) and
tert-BuOK (0.485 g, 4.32 mmol) were added and refluxing
was continued for further 10 min. The reaction mixture was
allowed to cool to room temperature diluted with ethyl
acetate (75 mL), saturated NH4Cl solution (50 mL) was
added and stirred at room temperature for 30 min. The
organic layer thus separated was washed with water
(2£100 mL), saturated NH4Cl (100 mL), dried over anhy-
drous sodium sulphate, filtered and concentrated under
vacuum to furnish crude exomethylene compound 10.
Column chromatography on silica gel (60–120 mesh,
eluent: ethyl acetate–petroleum ether 3:97) furnished pure
exomethylene compound 10 in 73% yield.
3. Conclusion
A convenient and practical total synthesis of (^)-b-
herbertenol has been achieved in 6.5% overall yield. The
formation of cyclopentadione 9 onto the aromatic moiety,
which is better than the reported synthesis, is the key feature
of this protocol. This methodology by virtue of involvement
of prochiral intermediate i.e. cyclopentadione 9 has a
potential to synthesize chiral compounds of this family by
chemical and/or enzymatic desymmetrization protocols.
Studies towards an asymmetric synthesis of b-herbertenol
are under progress and will be published in due course.
4. Experimental
4.1. General
1
Melting points were uncorrected. H and 13C NMR spectra
were recorded on 200 and 50 MHz in CDCl3 using TMS as
an internal standard. IR spectra were recorded in CHCl3 on
FT-IR spectrometer.

S. P. Chavan et al. / Tetrahedron 59 (2003) 2737–2741
2739
Yield 2.89 g (73%). Colorless thick syrup which solidified
upon standing. Mp 62–638C. IR (CHCl3) nmax (cm21):
2960, 2930, 1741, 1660, 1605, 1503, 1465, 1440, 1300,
d 16.07 (q), 24.37 (t), 31.39 (q), 32.50 (t), 49.11 (d), 53.52
(s), 54.9 (q), 63.04 (t), 79.03 (d), 109.76 (d), 126.01 (s),
126.21 (d), 130.57 (d), 135.05 (s), 155.53 (s). Mass (m/z):
250 (Mþ, 11), 232 (5), 217 (5), 189 (10), 175 (12), 149
(100), 135 (8), 115 (9), 91 (15), 77 (6). HRMS: Mþ, found
250.1573. C14H16O3 requires 250.1569.
1
1280, 1120, 895, 754. H NMR (CDCl3, 200 MHz) d: 1.42
(s, 3H) 2.20 (s, 3H), 2.25–2.48 (m, 2H), 2.59–2.67 (m, 2H),
3.81 (s, 3H), 5.12 (s, 1H), 5.33 (s, 1H), 6.76 (d, 1H, J¼
7.9 Hz), 7.11–7.16 (m, 2H). 13C NMR (CDCl3, 50 MHz) d:
16.00 (q), 22.91 (q), 27.5 (t), 34.03 (t), 54.71 (q), 60.71 (s),
109.73 (d), 109.81 (t), 124.63 (d), 126.73 (s), 128.41 (d),
132.72 (s), 153.18 (s), 156.82 (s), 212.85 (s). Mass (m/z):
230 (Mþ, 48), 187 (100), 173 (16), 159 (17), 144 (8), 128
(13), 115 (16), 105 (58), 91 (14), 77 (41). HRMS: Mþ, found
230.1311. C15H18O2 requires 230.1307.
4.1.4. Xanthate derivative [12]. To an ice-cold solution of
the diol 11 (1.53 g, 6.12 mmol.), Et3N (1.55 g, 2.12 mL,
15.3 mmol) and DMAP (catalytic) in dry DCM (45 mL) was
added pivaloyl chloride (0.886 g, 0.9 mL, 7.35 mmol)
dropwise. The reaction mixture was stirred at 08C. The
reaction was monitored by TLC. After completion of the
reaction, the reaction mixture was diluted with ethyl acetate
(25 mL) and washed with water (2£20 mL), brine (20 mL).
The organic layer was dried over anhydrous sodium
sulphate, filtered and concentrated under reduced pressure
to yield crude pivoloate ester. Column chromatography on
silica gel (60–120 mesh, eluent: ethyl acetate–petroleum
ether 12:88) yielded pure pivaloate ester as colorless oil.
Yield 1.67 g. (84%). IR (CHCl3) nmax (cm21): 3020, 2970,
4.1.3. 3-Hydroxymethyl-2-(4-methoxy-3-methylphenyl)-
2-methylcyclopentanol [11]. To the solution of ketoolefin 8
(2.028 g, 8.82 mmol) in ethanol (25 mL), NaBH4 (0.502 g,
13.22 mmol) was added portion wise over 10 min at room
temperature. Then the reaction mixture was stirred at room
temperature for 30 min further. The reaction was monitored
by TLC. After completion of the reaction, ethanol was
removed under reduced pressure. The crude residue thus
obtained was extracted with ethyl acetate. The organic layer
was washed with water (20 mL), brine (20 mL), dried over
anhydrous sodium sulphate, filtered and concentrated under
reduced pressure to furnish secondary alcohol as white
solid. The alcohol was purified by crystallization from ethyl
acetate–petroleum ether (5:95). Yield 2 g, (98%). White
solid. Mp 1288C. IR (CHCl3) nmax (cm21): 3450 (broad),
2960, 1650, 1630, 1500, 1410, 1385, 1220, 1140, 1035, 768.
1H NMR (CDCl3, 200 MHz): d 1.49 (s, 3H), 1.52–1.68 (m,
1H), 1.89–2.09 (m, 1H), 2.24 (s, 3H), 2.41–2.88 (m, 2H),
3.84 (s, 3H), 3.81–3.85 (m, 1H), 4.88 (s, 1H), 5.16 (s, 1H),
6.80 (d, 1H, J¼8.0 Hz), 7.17–7.21 (m, 2H). Mass (m/z): 232
(Mþ, 88), 214 (16), 199 (24), 189 (52), 173 (100), 157 (23),
149 (35), 115 (92), 91 (23), 77 (17).
1
1717, 1506, 1480, 1290, 1254, 1160, 765, 668. H NMR
(CDCl3, 200 MHz) d: 1.18 (s, 9H), 1.33 (s, 3H), 1.77–2.11
(m, 3H), 2.15–2.42 (m, 2H), 2.22 (s, 3H), 3.81 (s, 3H), 3.84
(dd, 1H, J¼9.3, 11.3 Hz), 4.15 (m, 2H), 6.80 (d, 1H, J¼
8.8 Hz), 7.11 (m, 2H). 13C NMR (CDCl3, 50 MHz) d: 16.19
(q), 25.49 (t), 27.00 (q, 3£–CH3), 28.83 (q), 31.44 (t), 38.47
(s), 46.92 (d), 52.69 (s), 55.04 (q), 66.36 (t), 80.59 (d),
110.03 (d), 126.46 (d), 130.43 (d), 132.86 (s), 156.05 (s),
178.15 (s). Mass (m/z): 334 (Mþ, 8), 232 (10), 217 (7), 199
(4), 189 (14), 175 (21), 162 (9), 149 (100), 135 (9), 115 (7),
91 (10), 77 (6).
The xanthate derivative 12 was prepared by using general
literature method. NaH (60% dispersion in oil, 0.3 g.,
7.5 mmol) was successively washed with dry hexane under
an inert atmosphere. To this, pivaloate ester (1.67 g,
5 mmol) in dry THF (16 mL) was added dropwise. The
reaction mixture was stirred at room temperature for 3 h,
then carbon disulphide (4 mL) was added dropwise. The
reaction mixture was stirred further for 3 h, methyl iodide
(2.13 g, 15 mmol) in dry THF (4 mL) was added. The
reaction mixture was stirred for an additional 16 h at room
temperature. The reaction was monitored by TLC. After the
completion of the reaction, THF was removed under
reduced pressure. The residue was extracted with ethyl
acetate (2£30 mL). The organic layer was washed with
water (2£15 mL), brine (15 mL), dried over anhydrous
sodium sulphate, filtered, concentrated in vacuum to furnish
crude xanthate derivative 12. Column chromatography on
silica gel (60–120 mesh, eluent: ethyl acetate–petroleum
ether 3:97) furnished xanthate 12 as colorless oil.
The diol 11 was obtained by hydroboration of cyclopentanol
with boranedimethylsulphide complex followed by oxi-
dative alkaline hydrolysis with H2O2. Thus to the solution of
cyclopentanol (2 g, 8.62 mmol) in dry THF (30 mL) at 08C,
BMS complex (2 M solution in THF, 1.638 g, 10.6 mL,
21.55 mmol) was added dropwise. The reaction mixture was
brought to room temperature and stirred overnight. The
reaction mixture was then cooled to 08C, 30% NaOH (8 mL)
was added in a single lot followed by H2O2 (30%, 8 mL)
dropwise. The reaction mixture was stirred at room
temperature for 30 min and then diluted with ethyl acetate.
The organic layer thus separated was washed with water
(2£30 mL), brine (30 mL), dried over anhydrous sodium
sulphate, filtered and concentrated under reduced pressure
to furnish crude diol 11. Column chromatography of the
diol on silica gel (60–120 mesh, eluent: ethyl acetate–
petroleum ether 25:75) furnished pure diol 11 as crystalline
white solid.
Yield 1.817 g (86%) IR (CHCl3) nmax (cm21): 3020, 1716,
1505, 1215, 1160, 770, 670. 1H NMR (CDCl3, 200 MHz) d:
1.21 (s, 9H), 1.34 (s, 3H), 1.84–2.18 (m, 3H), 2.21 (s, 3H),
2.31 (s, 3H), 2.48–2.66 (m, 2H), 3.81 (s, 3H), 3.82–3.96
(m, 1H), 4.24–4.28 (m, 1H), 5.98–6.02 (m, 1H), 6.76
(d, 1H, J¼8 Hz), 6.98–7.02 (m, 2H). 13C NMR (CDCl3,
50 MHz) d: 17.09 (q), 19.13 (q), 20.21 (t), 27.98 (q,
3£CH3), 30.49 (t), 31.16 (q), 39.46 (s), 47.82 (d), 53.86 (s),
55.94 (q), 66.99 (t), 91.83 (d), 110.51 (d), 120.62 (d), 126.72
(s), 130.90 (d), 134.31 (s), 156.72 (s), 179.06 (s), 215.13 (s).
Yield 1.53 g (71%). White solid. Mp 149–1518C. IR
(CHCl3) nmax (cm21): 3450 (broad), 3020, 1250, 1210,
761, 669. 1H NMR (CDCl3, 200 MHz): d1.24 (s, 3H), 1.77–
1.89 (m, 1H), 1.91–2.24 (m, 3H), 2.22 (s, 3H), 2.26–2.37
(m, 1H), 3.52 (dd, 1H, J¼3.9, 10.7 Hz,), 3.80 (dd, 1H, J¼
3.9, 10.7 Hz), 3.82 (s, 3H), 4.18–4.20 (m, 1H), 6.78 (d, 1H,
J¼9.0 Hz), 7.09–7.15 (m, 2H) 13C NMR (CDCl3, 50 MHz):

2740
S. P. Chavan et al. / Tetrahedron 59 (2003) 2737–2741
Mass (m/z): 424 (6), 316 (4), 231 (4), 215 (100), 199 (18),
187 (15), 173 (17), 135 (28), 91 (26), 77 (7).
successively washed with water (3£20 mL), brine
(2£20 mL). The organic layer was dried over anhydrous
sodium sulphate, filtered and concentrated under vacuum to
yield aldehyde 14.
4.1.5. Pivaloate ester [13]. This pivaloate ester was
obtained by deoxygenation of xanthate derivative 12.
Thus a mixture of xanthate derivative 12 (1.812 g,
4.27 mmol), tri-n-butyltinhydride (6.22 g, 5.66 mL,
21.37 mmol) and AIBN (catalytic) in dry toluene was
refluxed for 3 h. The reaction mixture was cooled to room
temperature and the reaction mixture was diluted with ethyl
acetate (50 mL). The excess of tri-n-butyltinhydride was
destroyed by aqueous KF (10% solution, 20 mL). The
organic layer was successively washed with aqueous KF
(10%, 3£20 mL), water (2£20 mL), brine (20 mL), dried
over anhydrous sodium sulphate, filtered and concentrated
in vacuum to furnish crude pivaloate ester. Column
chromatography on silica gel (60–120 mesh, eluent: ethyl
actetate–petroleum ether 1:99) furnished the pure pivaloate
ester 13. Yield 1.11 g (83%). IR (CHCl3) nmax (cm21):
Yield 0.359 g (86%). IR (CHCl3) nmax (cm21): 2960, 1703,
1611, 1505, 1250, 771, 670. 1H NMR (CDCl3, 200 MHz) d:
1.36 (s, 3H), 1.90–2.15 (m, 6H), 2.21 (s, 3H), 2.80–2.85
(m, 1H), 3.81 (s, 3H) 6.76 (d, 1H, J¼8 Hz), 7.05–7.08 (m,
2H),9.17 (d, 1H, J¼4 Hz). 13C NMR (CDCl3, 50 MHz) d:
15.64 (q), 21.78 (t), 24.57 (t), 29.79 (q), 36.85 (t), 48.69 (s),
54.53 (q), 60.71 (d), 109.12 (d), 124.33 (d), 125.73 (s),
128.56 (d), 136.72 (s), 155.39 (s), 203.73 (d). Mass (m/z):
232 (Mþ, 12), 189 (14), 175 (100), 162 (78), 147 (32), 137
(17), 115 (21), 105 (15), 91 (48), 77 (34).
4.1.7. 1-Methyl-2-(4-methoxy-3-methylphenyl)-2-
methylcyclopentane-1-carbaldehyde [15]. NaH (60%
dispersion in oil, 0.070 g, 1.65 mmol) was successively
washed with dry n-haxane (2£5 mL). To this, aldehyde 14
(0.320 g, 1.38 mmol) in dry DME (10 mL) was added
dropwise at 2108C. Hydrogen evolution was induced by
warming up the reaction mixture to 08C, stirred at 08C for
30 min. Methyl iodide (0.313 g, 2.2 mmol) in dry DME
(4 mL) was added dropwise. The reaction mixture was
stirred at 08C for 3 h and then at room temperature for 16 h.
Then the reaction mixture was poured into water (5 mL) and
extracted with diethyl ether (3£20 mL). The combined
organic layers were washed with brine and then dried over
anhydrous sodium sulphate, filtered and concentrated under
reduced pressure to furnish aldehyde 15. The column
chromatography on silica gel (60–120 mesh, eluent ethyl
acetate–petroleum ether 1:99) furnished the pure aldehyde.
1
3020, 1713, 1605, 1508, 1215, 1160, 770, 670. H NMR
(CDCl3, 200 MHz) d: 1.17 (s, 9H), 1.37 (s, 3H), 1.44–2.08
(m, 4H), 2.12–2.20 (m, 3H), 2.21 (s, 3H), 3.48 (dd, 1H,
J¼8.6, 2.5 Hz), 3.72 (dd, 1H, J¼J¼5.5 Hz), 3.81 (s, 3H),
6.74 (d, 1H, J¼8 Hz), 7.05–7.09 (m, 2H). 13C NMR
(CDCl3, 50 MHz) d: 16.14 (q), 21.65 (t), 26.91 (q, 3£CH3),
27.1 (t), 29.70 (q), 37.64 (d), 37.76 (s), 47.75 (s), 48.63 (d),
54.96 (q), 66.20 (t), 109.32 (d), 124.80 (d), 125.57 (s),
129.10 (d), 137.73 (s), 155.60 (s), 178.17 (s). HRMS: Mþ,
found 318.2193. C20H30O3 requires 318.2195.
4.1.6. 2-(4-Methoxy-3-methylphenyl)-2-methylcyclopen-
tane-1-carbaldehyde [14]. LiAlH4 (0.266 g, 7 mmol) was
added to THF solution (25 mL) of pivaloate ester 13 (1.11 g,
3.5 mmol) and stirred at room temperature. The reaction
was slightly exothermic and was monitored by TLC. After
the completion of reaction, THF was removed under
reduced pressure and the residue was extracted with diethyl
ether (3£25 mL). The organic layer was washed with dilute
HCl (5%, 20 mL), water (3£25 mL), brine (30 mL) dried
over anhydrous sodium sulphate, filtered and concentrated
under vacuum to yield crude alcohol. The column
chromatography on silica gel (60–120 mesh, eluent ethyl
acetate–petroleum ether 12:88) furnished the pure product
as colorless oil.
1
Yield 0.220 g (65%). H NMR (CDCl3, 200 MHz) d: 1.25
(s, 1.5H), 1.31 (s, 1.5H), 1.34 (s, 1.5H), 1.40 (s, 1.5H),
1.56–1.63 (m, 2H), 1.77–1.94 (m, 2H), 2.11–2.41 (m, 2H),
2.21 (s, 3H), 3.81 (s, 3H), 6.76 (d, 1H, J¼7.86 Hz), 7.09–
7.12 (m, 2H), 9.04 (s, 1H).
4.1.8. 1,1-Dimethyl-2-methyl-2-(4-methoxy-3-methyl-
phenyl)-2-methylcyclopentane [16]. A mixture of 15
(0.2 g,0.81 mmol), hydrazine hydrate (0.285 g, 0.35 mL,
5.69 mmol), NaOH (0.287 g, 7.15 mmol) and triethylene
glycol (5 mL) was heated at 1958C (oil bath temperature) for
7 h. After cooling to room temperature, water (5 mL) was
added and the mixture extracted with diethyl ether
(4£20 mL). The combined organic extracts were washed
with brine (20 mL), dried over anhydrous sodium sulphate,
filtered and concentrated to furnish compound 16. Column
chromatography on silica gel (60–120 mesh, eluent: ethyl
acetate–petroleum ether 1:99) furnished the pure product
16.
Yield 0.726 g. (92%). IR (CHCl3) nmax (cm21): 3450
(broad), 3020, 2910, 1205, 1160, 770, 668. 1H NMR
(CDCl3, 200 MHz) d: 1.34 (s, 3H), 1.61–1.72 (m, 2H),
1.74–1.99 (m, 3H), 2.02–2.18 (m, 2H), 2.22 (s, 3H), 3.02–
3.15 (m, 1H), 3.26–3.39 (m, 1H), 3.82 (s, 3H), 6.76 (d, 1H,
J¼8 Hz), 7.06–7.12 (m, 2H). 13C NMR (CDCl3, 50 MHz):
16.21 (q), 21.73 (t), 27.18 (t), 29.85 (q), 37.39 (t), 47.71 (s),
51.92 (d), 54.99 (q), 64.37 (t), 109.32 (d), 124.70 (d), 125.68
(s), 129.11 (d), 139.43 (s), 155.56 (s).
Yield 98 mg (52%). 1H NMR (CDCl3, 200 MHz) d:0.59 (s,
3H), 1.08 (s, 3H), 1.27 (s, 3H), 1.53–1.86 (m, 5H), 2.25 (s,
3H), 2.43–2.60 (m, 1H), 3.84 (s, 3H) 6.76 (d, 1H,
J¼7.9 Hz), 7.14–7.18 (m, 2H) 13C NMR (CDCl3,
50 MHz) d: 16.74 (q), 19.90 (t), 24.46 (q), 24.68 (q),
26.70 (q), 37.14 (t), 39.94 (t), 44.39 (s), 50.08 (s), 55.34 (q),
109.12 (d), 125.29 (d), 129.75 (d), 139.40 (s), 155.73 (s).
To an ice-cold solution of primary alcohol (0.421 g,
1.78 mmol) in dry dichloromethane (20 mL), pyridinium
chlorochromate (0.578 g, 2.67 mmol) was added in a single
portion. As the reaction proceeds, the orange colored
reaction mixture turned black. The reaction was monitored
by TLC. After completion of the reaction, diethyl ether
(30 mL) was added in order to precipitate out chromous
salts, filtered through a short bed of celite. The filtrate was
4.1.9. (6)-b-Herbertenol [5]. BBr3 (1 M solution in

S. P. Chavan et al. / Tetrahedron 59 (2003) 2737–2741
2741
Phytochemistry 1991, 30, 4019. (h) Nagashima, F.; Nishioka,
E.; Kameo, K.; Nakagawa, C.; Asakawa, Y. Phytochemistry
1991, 30, 215.
CH2Cl2, 0.251 g, ,1 mL, 1 mmol) was added dropwise to
methyl ether 16 (45 mg, 0.19 mmol) in dry CH2Cl2 (5 mL)
at 2788C. The reaction mixture was brought to room
temperature and stirred for 30 min. The reaction was
monitored by TLC. After completion, the reaction mixture
was diluted with CH2Cl2 (10 mL) and excess of BBr3 was
quenched with saturated NaHCO3 (1 mL). The organic layer
was washed with water, brine, dried over anhydrous sodium
sulfate, filtered and concentrated at reduced pressure to
furnish crude (^)-b-herbertenol 5. It was purified by
column chromatography (SiO2) (eluent: ethyl acetate–pet.
ether 5:95).
2. (a) Connolly, J. D.; Hill, R. A.; 1st ed. Dictionary of
Terpenoids; Chapman & Hall: London, 1991; Vol. 1. p 299.
(b) Fraga, B. M. Nat. Prod. Rep. 1998, 15, 73 and references
cited therein.
3. Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1
1991, 2737.
4. Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett.
1996, 37, 1261.
5. (a) Abad, A.; Agullo, C.; Cunat, C. A.; Perni, R. H. J. Org.
Chem. 1999, 64, 1741. (b) Abad, A.; Agullo, C.; Arno, M.;
Cunat, C. A.; Garcia, M. T.; Zaragoza, R. J. J. Org. Chem.
1996, 61, 5916. (c) Saha, A. K.; Das, S.; Mukherjee, D.
Tetrahedron Lett. 1994, 35, 3353. (d) Harrowven, D. C.;
Hannam, J. C. Tetrahedron Lett. 1998, 39, 9573. (e) Pal, A.;
Gupta, P. D.; Roy, A.; Mukherjee, D. Tetrahedron Lett. 1999,
40, 4733. (f) Mandelt, K.; Fitjer, L. Synthesis 1998, 1523. and
references cited therein.
Yield 34 mg (81%). Mp 85–868C (848C)6 IR (CHCl3) nmax
(cm21): 3450 (broad), 3020, 2960, 1610, 1215, 1106, 766,
1
670. H NMR (CDCl3, 200 MHz) d: 0.58 (s, 3H), 1.06 (s,
3H), 1.25 (s, 3H), 1.48–1.52 (m, 1H), 1.56–1.73 (m, 2H),
1.73–1.84 (m, 2H), 2.27 (s, 3H), 2.39–2.53 (m, 1H), 4.75
(bs, 1H), 6.72 (d, 1H, J¼7.9 Hz), 7.05–7.11 (m, 2H). 13C
NMR (CDCl3, 50 MHz) d: 16.29 (q), 20.02 (t), 24.57 (q),
24.84 (q), 26.79 (q), 37.32 (t), 40.13 (t), 44.49 (s), 50.26 (s),
114.29 (d), 122.59 (s), 125.92 (d), 129.98 (d), 140.20 (s),
151.77 (s). Mass (m/z): 218 (Mþ, 24), 161 (52), 148 (100),
135 (48), 121 (23), 91 (21), 77 (22), 55 (27). HRMS: Mþ,
found 218.1669. C20H30O3 requires 218.1671.
6. Eicher, T.; Servet, F.; Speicher, A. Synthesis 1996, 863.
7. (a) Chavan, S. P.; Patil, S. S.; Ravindranathan, T. Tetrahedron
1999, 55, 13417. (b) Chavan, S. P.; Ravindranathan, T.; Patil,
S. S.; Dhondge, V. D.; Dantale, S. W. Tetrahedron Lett. 1996,
37, 2629.
8. (a) Pandey, B.; Khire, U. R.; Ayyangar, N. R. Synth. Commun.
1989, 2741. (b) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem.
1976, 41, 2073.
Acknowledgements
9. Schulte-Elte, K. H.; Ohloff, G. Helv. Chim. Acta 1967, 50,
153.
RKK, RRK, DAK thank CSIR, New Delhi for fellowship.
Funding from Young Scientist Award, CSIR, New Delhi is
also gratefully acknowledged.
10. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703.
11. (a) Chen, S. H.; Huang, S.; Kant, J.; Fairchild, C.; Wei, J.;
Farina, V. J. Org. Chem. 1993, 58, 5028. (b) Nace, H. R. Org.
React. 1962, 12, 57. (c) Roberts, J. D.; Sauer, C. W. J. Am.
Chem. Soc. 1949, 71, 3925.
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