First enantiospecific synthesis of (+)-β-herbertenol

Article abstract of DOI:10.1016/j.tet.2005.01.050

The first enantiospecific synthesis of (+)-β-herbertenol, from naturally occurring R-(+)-citronellal, employing Taber's diazo decomposition protocol as the key step, is described.

Full text of DOI:10.1016/j.tet.2005.01.050

Tetrahedron 61 (2005) 3873–3879
First enantiospecific synthesis of (C)-b-herbertenol
a
a
a
Subhash P. Chavan,a, Mahesh Thakkar, Rajendra K. Kharul, Ashok B. Pathak,
*
Gaurav V. Bhosekarb and Mohan M. Bhadbhadeb
aDivision of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
bCenter for Materials Characterisation, National Chemical Laboratory, Pune 411008, India
Received 4 August 2004; revised 23 December 2004; accepted 14 January 2005
Abstract—The first enantiospecific synthesis of (C)-b-herbertenol, from naturally occurring R-(C)-citronellal, employing Taber’s diazo
decomposition protocol as the key step, is described.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
skeletons has led to the synthesis of cuparenones6i,j and
recently in the facile synthesis of (G)-b-herbertenol.6k In
continuation of our efforts towards the synthesis of
homochiral b-herbertenol, we describe herein the first
enantiospecific synthesis of (C)-b-herbertenol.
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
Recently, Asakawa and co-workers reported the isolation of
seven new herbertanes and two new cuperanes from
Japanese liverworts.3 Many of these compounds, particu-
larly those with an oxygenated aromatic six membered ring,
show a wide spectrum of biological properties, which
include potent antifungal, neurotrophic and anti-lipid
peroxidation activities (Fig. 1).1a,b,4,5
2. Results and discussion
The idea central to our synthetic route is to make use of
naturally occurring chiral citronellal for asymmetric syn-
thesis of b-herbertenol using Taber’s protocol of diazo
decomposition of a-diazo-b-ketoester 8 by Rh2(OAc)4 to
provide the five membered ring with retention of configu-
ration at the chiral center.7,8
To investigate the idea, R-(C)-citronellal was converted
into a-diazo-b-ketoester 8 as depicted in Scheme 1.
Enone 4a was synthesized from R-(C)-citronellal.9 It was
then converted into its silyl enol ether using LDA as base,10
and the resultant silyl enol ether was treated with NBS11 to
give the corresponding haloderivative 4b as a mixture of
diastereomers, and as we were going to destroy the centers
during aromatization in the next step, we did not establish
the diastereomeric ratio. Thus, the halo derivative 4b on
dehydrohalogenation12 provided the phenol 5a in 75%
overall yield. The phenol thus obtained was then protected
as methyl ether 5b and converted into acid 6, by Weinreb’s
method.13 Acid 6 was then converted into b-ketoester 7
using Meldrum’s acid in 78% yield. Diazotransfer was
carried out by Regitz’s protocol to give a-diazo-b-ketoester
8.14 The crucial insertion reaction was performed on 8
using rhodium catalyzed cyclization to furnish cyclized
b-ketoester 9 as a diastereomeric mixture in 40%
overall yield starting from 7. Having secured the key
Figure 1. Herbertene and cuparene skeleton.
Because of the difficulties associated with the construction
of the vicinal quaternary carbons in the cyclopentane ring,
herbertanes and cuparanes have become popular synthetic
targets in recent years.6 Although, there are synthetic
strategies reported towards (G)-b-herbertenol, not a single
asymmetric synthesis is reported. Our interest in these
Keywords: Enantiospecific; Diazo decomposition; Citronellal.
* Corresponding author. Tel.: C91 25893300 2289; fax: C91
2025893614; e-mail: spchavan@dalton.ncl.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.050

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S. P. Chavan et al. / Tetrahedron 61 (2005) 3873–3879
Scheme 1. Reagents and conditions: (a) (i) LDA, THF, K78 8C, TMSCl; (ii) NBS, THF, 0 8C, 0.5 h; (b) Li2CO3, LiBr, DMF, 135 8C, 4 h, 75% from 4a;
(c) K2CO3, Me2SO4, acetone, reflux, 12 h, 90%; (d) OsO4 (cat), Jones’ reagent, acetone, rt, 5 h, 80%; e) (i) SOCl2, CH2Cl2, reflux, 2 h; (ii) Meldrum’s acid,
pyridine, CH2Cl2, 0 8C–rt, 2 h; (iii) MeOH, reflux, 4 h, 78%; (f) Et3N, MsN3, CH2Cl2, K10 8C–rt, overnight; (g) Rh2(OAc)4 (cat.), CH2Cl2, rt, 40% for 2 steps;
(h) K2CO3, MeI, acetone, rt, 85%; (i) LAH, THF, 0 8C–rt, 5 h, 80%; (j) Pivaloyl chloride, Et3N, CH2Cl2, K10 8C–rt, 4 h, 65%; (k) NaH, CS2, THF, 0 8C, 1.5 h,
then MeI, rt, 5 h, 95%; (l) TBTH, AIBN (cat), toluene, reflux, 2 h, 80%; (m) LAH, THF, rt, 2 h, 95%; (n) (i) PDC, CH2Cl2, 0 8C, 3 h; (ii) NH2NH2–H2O,
diethyleneglycol, 150 8C, 4 h, 190 8C, 3 h, 73% for 2 steps; (o) BBr3, CH2Cl2, K78 8C–rt, overnight, 93%.
cyclopentanone in place, the remaining problem was to
convert 9 into the geminal dialkylated cyclopentane
skeleton. Accordingly, ester 9 was methylated using
K2CO3, MeI in dry acetone, which gave single diasteteomer
10 in which methyl group and the aryl group on the adjacent
alcohol 15. This alcohol was then oxidized to the
corresponding aldehyde using PDC, followed by deoxy-
genation under Huang–Minlon conditions to give the
methyl ether of b-herbertenol 16, which on deprotection
using BBr3 gave the final product, that is, (C)-b-herbertenol
17.
1
quaternary carbon are anti to each other. The H NMR
spectrum of the compound 10 support this, in which the
ester methyl signal appeared at 3.33 ppm because of the
shielding of methoxy carbonyl group by the vicinal cis aryl
group. The b-ketoester 10 was then reduced using LAH to
the corresponding diol 11 as a single diastereomer. The
stereochemistry of compound 11 was deduced by X-ray
analysis of the racemic alcohol diol 11 (Fig. 2). The X-ray
structure not only confirms the relative configuration of
newly generated hydroxy group in 11, but also the relative
stereochemistry of methyl group in 10. The primary alcohol
of diol 11 was protected as a pivaloyl ester to give 12. The
secondary alcohol group was then deoxygenated by
employing Barton’s protocol15 to give pivaloyl ester 14,
which on reduction using LAH gave the corresponding
3. Conclusion
Thus, (C)-b-herbertenol has been synthesized from natu-
rally occurring R-(C)-citronellal employing carbene inser-
tion as the key step. The same idea can be applicable to the
synthesis of naturally occurring (K)-b-herbertenol and
other herbertanes.
4. Experimental
4.1. General methods
All solvents were freshly distilled before use and dry
solvents were distilled under argon from Na/benzophenone.
Melting points are uncorrected. Chemical shifts in H and
1
13C NMR are reported relative to residual solvents.
1
Abbreviations for H NMR: sZsinglet, dZdoublet, mZ
multiplet. Progress of the reactions were monitored by TLC
using Merck silica gel 60 F254 precoated plates and
visualized by flourescence quenching or by charring after
treatment with the mixture of p-anisaldehyde-H2SO4 in
ethanol. The products were purified by column chromato-
graphy (SiO2). Analytical data of all known compounds
were compared with the literature, and new compounds
were fully characterized.
Figure 2. ORTEP view of rac-11.

S. P. Chavan et al. / Tetrahedron 61 (2005) 3873–3879
3875
4.1.1. 6-Bromo-4-(1,5-dimethyl-hex-4-enyl)-6-methyl-
cyclohex-2-enone (4b). A 1 L round bottomed flask
equipped with a magnetic stir bar and a condenser was
charged with diisopropylamine (18.01 g, 178 mmol) and
dry THF (250 mL) under N2, and cooled to K78 8C. To this
mixture, n-BuLi (102.5 mL of a 1.6 M solution in hexane,
164 mmol) was added dropwise and stirred for 10 min,
followed by dropwise addition of the conjugated ketone
(30 g, 136 mmol) in dry THF (50 mL). Reaction mixture
was stirred for 1.5 h at K78 8C and then quenched with
chlorotrimethylsilane (16.296 g, 150 mmol). The reaction
mixture was allowed to come to 0 8C within 4 h and
quenched with saturated NaHCO3 solution (200 mL). The
mixture was extracted with pet ether (250 mL!3) and
combined organic layer was washed with brine solution,
dried over anhydrous Na2SO4, filtered and concentrated to
give 38 g of crude silyl enol ether, which was confirmed by
1H NMR and used directly for the next step. 1H NMR
(CDCl3, 200 MHz) d 0.15 (s, 9H), 0.84–0.89 (m, 3H), 1.17–
1.36 (m, 3H), 1.58 (s, 3H), 1.62 (s, 3H), 1.66 (s, 3H), 1.90–
2.08 (m, 4H), 2.21–2.26 (m, 1H), 5.06 (t, JZ6.4 Hz, 1H),
5.45–5.53 (m, 1H), 5.60–5.66 (m, 1H).
(CH2), 115.1 (CH), 123.8 (CH), 125.0 (CH), 125.6 (C),
129.9 (CH), 131.4 (C), 140.1 (C), 151.9 (C). MS-ESI m/z
218 (MC). Anal. Calcd for C15H22O: C, 82.52%; H,
10.16%. Found: C, 82.31%; H, 10.19%.
4.1.3. 4-(1,5-Dimethyl-hex-4-enyl)-1-methoxy-2-methyl-
benzene (5b). To a stirred solution of phenol (5a) (21 g,
96 mmol) in dry acetone (200 mL) was added anhydrous
K2CO3 (33.28 g, 241 mmol) and dimethyl sulphate
(30.38 g, 241 mmol) under N2. The mixture was refluxed
for 12 h and then acetone was removed under reduced
pressure followed by dilution with water. The mixture was
stirred overnight and then extracted with CH2Cl2
(200 mL!3). The combined organic layer was washed
with water, brine solution and dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
The product was purified by flash column chromatography
using pet. ether/EtOAc 99:1 as eluent to provide the methyl
ether 5b (20.2 g, 90%) as colorless oil. [a]2D5ZK44.2 (cZ
1.3, CHCl3); IR (neat) nmax (cmK1): 2957, 1609, 1505,
1463, 1376, 1251, 1135. 1H NMR (CDCl3, 200 MHz) d 1.20
(d, JZ6.8 Hz, 3H), 1.50–1.60 (m, 2H), 1.55 (s, 3H), 1.70 (s,
3H), 1.83–1.94 (m, 2H), 2.23 (s, 3H), 2.60 (m, 1H), 3.80 (s,
3H), 5.10 (t, JZ5.9 Hz, 1H), 6.74 (d, JZ8.8 Hz, 1H), 6.94–
6.98 (m, 2H). 13C NMR (CDCl3, 50 MHz) d 16.6 (CH3),
17.9 (CH3), 22.9 (CH3), 26.0 (CH3), 26.5 (CH2), 38.9 (CH),
38.9 (CH2), 55.4 (CH3), 110.0 (CH), 125.1 (CH) 125.2
(CH), 126.5 (C), 129.7 (CH), 131.3 (C), 139.5 (C), 156.2
(C). MS-ESI m/z 231 (MK1)C. Anal. Calcd for C16H24O:
C, 82.71%; H, 10.41%. Found: C, 82.58%; H, 10.80%.
To an ice-cold solution of crude silyl enol ether (38 g) in dry
THF (300 mL) was added N-bromosuccinimide (26.7 g,
150 mmol) portionwise and reaction mixture was stirred for
30 min at 0 8C and quenched with saturated NaHCO3
solution (300 mL). The reaction mixture was then extracted
with pet. ether (300 mL!2) and combined organic layer
was washed with brine solution, dried over anhydrous
Na2SO4 and concentrated to give 37 g of crude a-bromo
enone 4b, which was directly used for the dehydrohalo-
genation. IR (neat) nmax (cmK1): 2964, 1688, 1504, 1446,
1377, 1259.1H NMR (CDCl3, 200 MHz) d 0.84 (d, JZ
7.33 Hz, 1.5H), 0.87 (d, JZ7.33 Hz, 1.5H), 1.16–1.40 (m,
2H), 1.56 (s, 3H), 1.63 (s, 3H), 1.71–1.78 (m, 2H), 1.81 (s,
3H), 1.89–2.05 (m, 2H), 2.14–2.27 (m, 1H), 2.60–2.74 (m,
1H), 5.02 (t, JZ6.8 Hz, 1H), 5.92–5.99 (m, 1H), 6.69–6.78
(m, 1H). MS-ESI m/z 301 (MC2)C. Anal. Calcd for
C15H23BrO: C, 60.21%; H, 7.75%. Found: C, 60.47%; H,
7.49%.
4.1.4. 4-(4-Methoxy-3-methyl-phenyl)-pentanoicacid (6).
A 500 mL round bottomed flask equipped with magnetic stir
bar and 100 mL addition funnel was charged with olefin 5b
(16.34 g, 70.4 mmol) and acetone (200 mL). The mixture
was cooled to 0 8C and catalytic amount of OsO4 (2 mL of
1% solution in toluene) was added to it, which was stirred
for 15 min followed by dropwise addition of Jones’ reagent
(94 mL). The reaction mixture was stirred at room
temperature for 5 h before excess of Jones’ reagent was
quenched by isopropanol (15 mL). Acetone was removed
under reduced pressure followed by dilution with water and
extraction with CH2Cl2 (150 mL!3). The combined
organic layer was washed with water and brine solution,
dried over anhydrous Na2SO4, filtered and concentrated.
The product was purified by flash column chromatography
using pet. ether/EtOAc 9:1 as eluent to give acid 6 (12.5 g,
80%) as colorless oil. [a]2D5ZK19.5 (cZ0.8, CHCl3). IR
(neat) nmax (cmK1): 2957, 1709, 1610, 1507, 1456, 1377,
4.1.2. 4-(1,5-Dimethyl-hex-4-enyl)-2-methyl-phenol (5a).
To a solution of crude a-bromo enone in dry DMF (300 mL)
under N2 was added lithium carbonate (30.23 g, 409 mmol)
and lithium bromide (23.69 g, 273 mmol) and the mixture
was stirred at 130–135 8C for 3 h. The mixture was allowed
to come to room temperature and DMF was removed under
reduced pressure. The residue was diluted with water
(300 mL) and extracted with CH2Cl2 (300 mL!3). The
combined organic layer was washed with water (600 mL!
2) and brine solution (600 mL!1), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
The residue obtained was chromatographed using flash
silica gel (pet. ether: EtOAc 96:4 as eluent) to provide
phenol 5a (22.2 g, 75% overall) as colorless oil. [a]2D5Z
K39.1 (cZ0.92, CHCl3); IR (neat) nmax (cmK1): 3416,
2961, 1611, 1509, 1453, 1260. 1H NMR (CDCl3, 200 MHz)
d 1.19 (d, JZ6.8 Hz, 3H), 1.52 (s, 3H), 1.49–1.60 (m, 2H),
1.67 (s, 3H), 1.80–1.88 (m, 2H), 2.23 (s, 3H), 2.58 (m, 1H),
5.07 (t, JZ5.9 Hz, 1H), 6.66 (d, JZ7.8 Hz, 1H), 6.87–6.92
(m, 2H). 13C NMR (CDCl3, 50 MHz) d 16.1 (CH3), 17.9
(CH3), 22.9 (CH3), 25.9 (CH3), 26.5 (CH2), 38.9 (CH), 38.9
1
1252, 1182. H NMR (CDCl3, 500 MHz) d 1.27 (d, JZ
6.9 Hz, 3H), 1.84–1.97 (m, 2H), 2.23 (s, 3H), 2.24–2.26 (m,
2H), 2.67 (m, 1H), 3.82 (s, 3H), 6.75 (d, JZ8.2 Hz, 1H),
6.95–6.97 (m, 2H). 13C NMR (CDCl3, 125 MHz) d 16.5
(CH3), 22.8 (CH3), 32.6 (CH2), 33.4 (CH2), 38.8 (CH), 55.5
(CH3), 110.1 (CH), 125.3 (CH), 126.8 (C), 129.5 (CH),
137.9 (C), 156.5 (C), 180.6 (C). MS-ESI m/z 221 (MK1)C.
Anal. Calcd for C13H18O3: C, 70.24%; H, 8.16%. Found: C,
70.44%; H, 8.33%.
4.1.5. 6-(4-Methoxy-3-methyl-phenyl)-3-oxo-heptanoic-
acidmethylester (7). To a solution of acid (6) (14 g,
63 mmol) in dry CH2Cl2 (150 mL) was added thionyl
chloride (9 g, 75.6 mmol) and catalytic amount of DMF

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S. P. Chavan et al. / Tetrahedron 61 (2005) 3873–3879
(0.5 mL), under N2. The reaction mixture was refluxed for
2 h and then CH2Cl2 was removed at atmospheric pressure.
To remove the excess of thionyl chloride, dry benzene
(25 mL) was added to the residue and distilled off under
reduced pressure. The residue was as such used for the next
step.
ceased (30 min). The reaction mixture was concentrated in
vacuo and product was purified by flash column chroma-
tography using pet. ether/EtOAc 93:7 as eluent to give
cyclized b-keto ester (9) (3.13 g, 40% yield) as colorless oil.
IR (neat) nmax (cmK1): 2954, 1758, 1728, 1652, 1612, 1508,
1444, 1347, 1252, 1147. HRMS: MC, C16H20O4 requires
276.1361, found 276.1363. As this product was unstable, it
was used immediately for the next step.
A 500 mL round-bottomed flask equipped with stir bar was
charged with Meldrum’s acid (9.54 g, 66.3 mmol) and dry
CH2Cl2 (150 mL) under N2. The mixture was cooled to
K5 8C and pyridine (12.46 g, 158 mmol) was added to it.
After stirring for 30 min at 0 8C, acid chloride in dry CH2Cl2
(20 mL) was added dropwise to it. The mixture was stirred
at 0 8C for 1 h and at room temperature for an additional
hour followed by dilution with CH2Cl2. The reaction
mixture was poured to 2 N HCl solution (175 mL) contain-
ing crushed ice and aqueous layer was extracted with
CH2Cl2 (150 mL!2). The combined organic layer was
washed with 2 N HCl solution, water and finally with brine
solution, dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure to give crude acyl
meldrum derivative, which was taken in dry methanol
(300 mL) and refluxed for 4–5 h. Methanol was concen-
trated under reduced pressure and residue was chromato-
graphed using flash silica gel (pet. ether/EtOAc 92:8 as
eluent) to give b-keto ester (13.67 g, 78%) as yellow oil.
[a]2D5ZK19.9 (cZ1.95, CHCl3). IR (neat) nmax (cmK1):
2955, 1747, 1718, 1505, 1453, 1306, 1252. 1H NMR
(CDCl3, 200 MHz) d 1.23 (d, JZ6.2 Hz, 3H), 1.69–2.12 (m,
2H), 2.30–2.54 (m, 2H), 2.18 (s, 3H), 2.56–2.66 (m, 1H),
3.33 (s, 2H), 3.69 (s, 3H), 3.79 (s, 3H), 6.74 (d, JZ8.8 Hz,
1H), 6.89–6.92 (m, 2H). 13C NMR (CDCl3, 50 MHz) d 16.3
(CH3), 22.7 (CH3), 31.7 (CH2), 38.3 (CH), 41.1 (CH2), 48.8
(CH2), 51.9 (CH3), 55.0 (CH3), 109.7 (CH), 124.9 (CH),
126.3 (C), 129.1 (CH), 137.7 (C), 158.1 (C), 167.4 (C),
202.3 (C). MS-ESI m/z 279 (MC1)C. Anal. Calcd for
C16H22O4: C, 69.04%; H, 7.97%. Found: C, 69.04%; H,
8.16%.
4.1.7. 2-(4-Methoxy-3methyl-phenyl)-1,2-dimethyl-5-
oxo-cyclopentanecarboxylic acid methyl ester (10). To a
solution of b-keto ester 9 (1.5 g, 5.44 mmol) in dry acetone
(20 mL) was added anhydrous K2CO3 (0.751 g,
5.44 mmol), followed by iodomethane (0.41 mL,
6.52 mmol) under N2 at 20 8C and reaction mixture was
stirred at room temperature for 24 h. Reaction mixture was,
then, filtered through celite, solvent was evaporated under
reduced pressure and residue was then chromatographed
using flash silica gel (eluent; pet. ether/EtOAc 94:6) to give
the desired product 10 (1.34 g, 85% yield) as colorless oil.
[a]2D5ZC126.3 (cZ0.6, CHCl3); IR (neat) nmax (cmK1):
1
2952, 1745, 1713, 1511, 1454, 1383, 1300, 1253, 1141. H
NMR (CDCl3, 200 MHz) d 1.29 (s, 3H), 1.40 (s, 3H), 1.88–
2.80 (m, 4H), 2.22 (s, 3H), 3.33 (s, 3H), 3.82 (s, 3H), 7.01–
7.17 (m, 2H), 7.76 (d, JZ7.8 Hz, 1H). 13C NMR (CDCl3,
50 MHz) d 14.9 (CH3), 16.6 (CH3), 25.7 (CH3), 31.5 (CH2),
35.7 (CH2), 49.4 (C), 51.7 (CH3), 55.1 (CH3), 64.7 (C),
109.5 (CH), 124.1 (CH), 126.1 (CH), 128.3 (C), 135.9 (C),
156.5 (C), 171.1 (C), 215.5 (C). MS-ESI m/z 291 (MC1)C.
Anal. Calcd for C17H22O4: C, 70.30%; H, 7.64%. Found: C,
70.10%; H, 7.34%.
4.1.8. 2-Hydroxymethyl-3-(4-methoxy-3-methyl-phe-
nyl)2,3-dimethyl-cyclopentandiol (11). A 50 mL two
neck round-bottomed flask equipped with magnetic stir
bar was charged with LAH (0.328 g, 8.6 mmol) and dry
THF (10 mL) under N2. Reaction mixture was cooled to
0 8C and ketoester 10 was added to it using dry THF
(10 mL). It was stirred for additional 5 h at room
temperature, cooled to 0 8C and excess of LAH was
quenched by dilute HCl solution. THF was evaporated
under reduced pressure and aqueous layer was extracted
with CH2Cl2 (25 mL!3). The combined organic layer was
washed with water (50 mL!2), brine solution (50 mL),
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The product was purified by flash
column chromatography using pet ether/EtOAc 8:2 as
eluent to give diol 11 (0.725 g, 80% yield) as white solid.
MP 133–134 8C. [a]D25ZC58.7 (cZ1.1, CHCl3); IR
(CHCl3) nmax (cmK1): 3625, 3350, 3017, 2966, 1506,
4.1.6. 2-(4-Methoxy-3-methyl-phenyl)-2-methyl-5-oxo-
cyclopentanecarboxylic acid methylester (9). A 500 mL
round-bottomed flask equipped with a magnetic stir bar was
charged with ketoester (7) (9 g, 32.37 mmol) in dry CH2Cl2
(175 mL) and triethylamine (8.19 g, 80.9 mmol). The
reaction mixture was cooled to K5 8C and mesyl azide
(4.7 g, 38.8 mmol) in CH2Cl2 (25 mL) was added, dropwise.
The reaction mixture was stirred overnight at room
temperature, cooled to 0 8C and quenched with 5 M
NaOH solution (100 mL); and extracted using CH2Cl2
(100 mL!2). The combined organic layer was dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The product, a-diazo-b-keto ester, was purified by
filtering it through a short pad of silica gel using pet. ether/
EtOAc 9:1 as eluent and confirmed by IR. IR (neat) nmax
(cmK1): 2956, 2136, 1724, 1656, 1616, 1506, 1375, 1252,
1136.
1
1251. H NMR (CDCl3, 200 MHz) d 1.19 (s, 3H), 1.21 (s,
3H), 1.51–1.80 (m, 2H), 2.20 (s, 3H), 2.63–2.89 (m, 2H),
3.59 (d, JZ11.2 Hz, 1H), 3.76 (d, JZ11.2 Hz, 1H), 3.80 (s,
3H), 4.22 (dd, JZ6.4, 8.8 Hz, 1H), 6.71 (d, JZ9.3 Hz, 1H),
7.08 (m, 2H). 13C NMR (CDCl3, 50 MHz) d 16.9 (CH3),
17.4 (CH3), 27.0 (CH3), 30.9 (CH2), 34.2 (CH2), 48.9 (C),
50.2 (C), 55.4 (CH3), 67.6 (CH2), 82.7 (CH), 109.6 (CH),
125.0 (CH), 126.1 (C), 129.3 (CH), 137.4 (C), 156.2 (C).
MS-ESI m/z 265 (MC1)C. Anal. Calcd for C16H24O3: C,
72.69%; H, 9.15%. Found: C, 72.36%; H, 9.01%.
The oil was transferred to a flame dried 1 L round-bottomed
flask equipped with a magnetic stir bar and maintained
under N2. CH2Cl2 (500 mL), dried by filtering through
anhydrous K2CO3 was added, followed by rhodium (II)
acetate dimer (0.150 g, 2% by weight). The reaction mixture
was stirred at room temperature until evolution of nitrogen
Diffraction analysis of racemic (11) (C16H24O3, MZ
264.35). Single crystal of compound X obtained from

S. P. Chavan et al. / Tetrahedron 61 (2005) 3873–3879
3877
ethyl acetate–petroleum ether mixture. X-ray intensity data
were collected on a Bruker SMART APEX CCD diffracto-
meter with graphite-monochromatized (Mo KaZ
methyl-phenyl)-1,2-dimethyl-5-methylsulfanylthio-
caboxyoxy-cyclopentylmethyl ester (13). A 50 mL two-
necked round-bottomed flask equipped with a magnetic stir
bar was charged with NaH (60%) (0.12 g, 3 mmol) and dry
THF (7 mL). Alcohol (11) (0.7 g, 2 mmol) in dry THF
(7 mL) was added to it at 08 under N2 and reaction mixture
was stirred for 30 min. Then, carbon disulphide (0.23 g,
3 mmol) was added to it at 0 8C and stirred for 2 h at room
temperature followed by addition of iodomethane (0.85 g,
6 mmol) at 0 8C. The reaction mixture was stirred for
additional 5 h at room temperature. After completion of
reaction, mixture was diluted with ice water and extracted
with ethyl acetate (20 mL!3). The combined organic layer
was washed with water and brine solution, dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The product was purified by flash column
chromatography using pet. ether/EtOAc 98:2 as eluent to
give xanthate derivative (0.83 g, 94%) as colorless oil.
[a]2D5ZC11.4 (cZ1.6, CHCl3). IR (neat) nmax (cmK1):
2971, 1725, 1608, 1508, 1479, 1397, 1252, 1151. 1H NMR
(CDCl3, 500 MHz): d 1.16 (s, 3H), 1.16 (s, 9H), 1.39 (s, 3H),
1.76–1.82 (m, 1H), 1.90–1.96 (m, 1H), 2.19 (s, 3H), 2.30 (s,
3H), 2.55–2.63 (m, 1H), 2.76–2.82 (m, 1H), 3.59 (d, JZ
11.1 Hz, 1H), 3.80 (s, 3H), 3.86 (d, JZ11.1 Hz, 1H), 5.75
(dd, JZ4.8, 8.8 Hz, 1H), 6.72 (d, JZ8.3 Hz, 1H), 7.08–7.11
(m, 2H). 13C NMR (CDCl3, 125 MHz): d 16.9 (CH3), 18.7
(CH3), 19.0 (CH3), 26.7 (CH3), 27.6 (CH3), 29.6 (CH2), 36.4
(CH2), 49.9 (C), 51.3 (C), 55.5 (CH3), 66.8 (CH2), 92.2
(CH), 109.6 (CH), 116.4 (C), 125.7 (CH), 126.0 (C), 129.9
(CH), 136.7 (C), 156.5 (C), 178.2 (C), 215.1 (C). MS-ESI
m/z 440 (MC2)C. Anal. Calcd for C23H34O4S2. C, 62.97%;
H, 7.81%. Found: C, 63.32%; H, 7.53.
˚
0.71073 A) radiation at room temperature. All the data
were corrected for Lorentzian, polarization and absorption
effects using Bruker’s SAINT and SADABS programs.
SHELX-97 (G. M. Sheldrick, SHELX-97 program for
crystal structure solution and refinement, University of
Gottingen, Germany, 1997) was used for structure solution
and full matrix least squares refinement on F2. Hydrogen
atoms were included in the refinement as per the riding
model. Crystal data: crystal size, 0.40!0.19!0.12 mm3;
temperature, 293(2) K; crystal system, triclinic; spce group
˚
˚
˚
P1; aZ7.606(5) A; bZ9.793(6) A; cZ10.946(7) A; aZ
103.240(12)8; bZ107.106(11)8; gZ96.723(15)8; VZ
3
743.5(8) A ; ZZ2; F(000)Z288; d calc [g cmK3]Z1.181;
˚
m [mmK1]Z0.0808; absorption correction, multi-scan;
TminZ0.9688; TmaxZ0.9905; reflection collected, 7089;
unique reflections, 5082; observed reflections, 3305; index
range, K9%h%9, K11%k%11, K12%l%12; R1 [IO
2s(I)]Z0.0577; WR2Z0.1323; goodness of fit, 1.004;
Drmax, Drmin (e AK3)ZK0.155, 0.160. Crystallographic
˚
data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication
numbers CCDC-254163. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: 144 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Johnson, C.K, ORTEP III, report ORNL-5138, Oak Ridge
National Laboratory, Tenesse, USA (1976). (Incorporated
in SHELX TL package from Bruker-axs).
4.1.11. 2,2-Dimethyl-propionic acid 2-(4-methoxy-3-
methyl-phenyl)-1,2-dimethyl-cyclopentylmethyl ester
(14). To a stirred solution of xanthate (13) (0.53 g,
1.21 mmol) in dry toluene (20 mL) was added tributyltin-
hydride (0.39 g, 1.33 mmol) and AIBN (0.020 g, catalytic)
under N2. The mixture was stirred at reflux temperature for
2 h, the solvent was removed under reduced pressure and
residue was chromatographed using flash silica gel (pet.
ether/EtOAc 98:2 as eluent) to give required product
(0.32 g, 80% yield) as colorless oil. [a]2D5ZC16.7 (cZ
1.05, CHCl3). IR (neat) nmax (cmK1): 2966, 1728, 1608,
1508, 1464, 1382, 1252, 1156. 1H NMR (CDCl3, 500 MHz)
d 1.11 (s, 3H), 1.17 (s, 9H), 1.34 (s, 3H), 1.48–1.84 (m, 6H),
2.19 (s, 3H), 3.29 (d, JZ11.1 Hz, 1H), 3.63 (d, JZ11.1 Hz,
1H), 3.79 (s, 3H), 6.72 (d, JZ9.5 Hz, 1H), 7.10–7.14 (m,
2H). 13C NMR (CDCl3, 125 MHz) d 16.9 (CH3), 19.9
(CH3), 20.7 (CH2), 25.5 (CH3), 27.6 (CH3), 35.2 (CH2), 38.3
(CH2), 39.1 (C), 48.1 (C), 49.9 (C), 55.5 (CH3), 70.9 (CH2),
109.6 (CH), 125.3 (CH), 125.9 (C), 129.7 (CH), 137.9 (C),
156.3 (C), 178.5 (C). MS-ESI m/z 231 (MKOPiv.)C. Anal.
Calcd for C21H32O3: C, 75.86%; H, 9.7%. Found; C,
75.46%; H, 9.76%.
4.1.9. 2,2-Dimethyl-propionicacid 5-hydroxy-2-(4-meth-
oxy-3-methyl-phenyl)-1,2-dimethyl-cyclopentylmethyl
ester (12). To a solution of diol 11 (0.59 g, 2.24 mmol) in
dry CH2Cl2 (20 mL) was added triethylamine (0.27 g,
2.68 mmol), followed by cooling to K10 8C and addition
of pivaloyl chloride (0.28 g, 2.35 mmol) in dry CH2Cl2
(5 mL). Reaction mixture was stirred at 0 8C for 2.5 h and
diluted with water (50 mL). The aqueous layer was
extracted using CH2Cl2 (25 mL!3), the combined organic
layer was washed with brine solution, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
The product was purified by flash column chromatography
using pet. ether/EtOAc 9:1 as eluent to provide correspond-
ing pivaloyl ester 12 (0.51 g, 65%) as colorless oil.
[a]2D5ZC23.54 (cZ0.9, CHCl3). IR (neat) nmax (cmK1):
3407, 3018, 2972, 1718, 1608, 1504, 1465, 1288, 1157. 1H
NMR (CDCl3, 500 MHz) d 1.09 (s, 3H), 1.17 (s, 9H), 1.31
(s, 3H), 1.64–1.78 (m, 2H), 2.18 (s, 3H), 2.33–2.41 (m, 1H),
2.66–2.72 (m, 1H), 3.73 (d, JZ11.5 Hz, 1H), 3.76 (d, JZ
11.5 Hz, 1H), 3.80 (s, 3H), 4.08 (dd, JZ4.8, 8.7 Hz, 1H),
6.72 (d, JZ8.4 Hz, 1H), 7.12–7.15 (m, 2H). 13C NMR
(CDCl3, 125 MHz) d 16.9 (CH3), 18.5 (CH3), 27.0 (CH3),
27.5 (CH3), 31.7 (CH2), 35.0 (CH2), 39.1 (C), 49.3 (C), 51.2
(C), 55.4 (CH3), 68.0 (CH2), 81.6 (CH), 109.6 (CH), 125.3
(CH), 126.1 (C), 129.7 (CH), 137.6 (C), 156.3 (C), 178.6
(C). MS-ESI m/z 349 (MC1)C. Anal. Calcd for C21H32O4:
C, 72.38%; H, 9.26%. Found: C, 72.74%; H, 8.96%.
4.1.12. [2-(4-Methoxy-3methyl-phenyl)-1,2-dimethyl-
cyclopentyl]-methanol (15). To a stirred solution of ester
14 (0.3 g, 0.9 mmol) in dry THF (10 mL) was added LAH
(0.69 g, 1.8 mmol) portionwise at room temperature and
reaction mixture was stirred at room temperature for 12 h.
After completion of the reaction, excess of LAH was
quenched with dilute HCl solution, THF was evaporated
4.1.10. 2,2-Dimethyl-propionic acid 2-(4-methoxy-3-

3878
S. P. Chavan et al. / Tetrahedron 61 (2005) 3873–3879
under reduced pressure and aqueous layer was extracted
using CH2Cl2 (30 mL!3). The combined organic layer was
washed with water and brine solution, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
The product was purified by flash column chromatography
using pet. ether/EtOAc 9:1 as eluent to give alcohol 15
(0.22 g, quantitative yield) as colorless oil. [a]2D5Z42.1 (cZ
0.75, CHCl3). IR (neat) nmax (cmK1): 3378, 2954, 1608,
1506, 1464, 1376, 1296, 1172. 1H NMR (CDCl3, 200 MHz)
d 1.14 (s, 3H), 1.30 (s, 3H), 1.48–1.87 (m, 6H), 2.22 (s, 3H),
3.06 (d, JZ11.1 Hz, 1H), 3.15 (d, JZ11.1 Hz, 1H), 3.82 (s,
3H), 6.76 (d, JZ8.4 Hz, 1H), 7.07–7.17 (m, 2H). 13C NMR
(CDCl3, 50 MHz) d 16.9 (CH3), 19.7 (CH3), 20.5 (CH2),
25.5 (CH3), 35.2 (CH2), 37.7 (CH2), 49.3 (C), 49.4 (C), 55.4
(CH3), 69.6 (CH2), 109.6 (CH), 125.1 (CH), 126.1 (C),
129.4 (CH), 138.1 (C), 156.2 (C). MS-ESI m/z 230 (MK
H2O)C. Anal. Calcd for C16H24O2. C, 77.38%; H, 9.74%.
Found: C, 77.19%; H, 9.58%.
was washed with water, brine, dried over anhydrous sodium
sulphate, filtered and concentrated at reduced pressure to
furnish crude (C)-b-herbertenol. It was purified by flash
column chromatography (pet. ether/EtOAc 95:5 as eluent)
to give pure (C)-b-herbertenol. (0.039 g, 93%). MP 79–
80 8C. [a]2D5ZC61.2 (cZ0.7, CHCl3). IR (CHCl3) nmax
1
(cmK1) 3450 (broad), 3020, 2960, 1610, 1215, 1106. 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, JZ7.9 Hz 1H), 7.05–7.11 (m, 2H). 13C NMR (CDCl3,
50 MHz) d 16.3 (CH3), 20.0 (CH2), 24.6 (CH3), 24.8 (CH3),
26.8 (CH3), 37.3 (CH2), 40.1 (CH2) 44.5 (C), 50.3 (C), 114.3
(CH), 122.6 (C), 125.9 (CH), 129.9 (CH), 140.2 (C), 151.8
(C). Mass m/z 218 (MC). HRMS: MC, found 218.1669.
C15H22O requires 218.1671. [For (K)-b-herbertenol; MP
80–81 8C and [a]2D5ZK47 (c 0.7, CHCl3)].
4.1.13. 1-Methoxy-2-methyl-4-(1,2,2-trimethyl-cyclopen-
tyl)-benzene (16). To a stirred solution of alcohol (15)
(0.1 g, 0.4 mmol) in dry CH2Cl2 (10 mL) was added
pyridinium dichromate (0.228 g, 0.6 mmol) portionwise at
0 C within 5 min and allowed to stir at room temperature for
3 h. Reaction mixture was then diluted with diethyl ether
(25 mL) and filtered through a short pad of celite, which was
washed with diethyl ether (25 mL!2). Organic layer was
then washed with water and brine solution, dried over
sodium sulphate and concentrated. The residue (0.11 g) was
Acknowledgements
We profoundly thank Takasago International Corporation,
Japan for generous gift of R-(C)-citronellal. MRT, RKK
and ABP thank CSIR for fellowship. Funding from YSA
(CSIR), New Delhi, INDIA to S.P.C. is gratefully
acknowledged.
1
directly used for the next step, as aldehyde is unstable. H
References and notes
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, JZ7.86 Hz), 7.09–7.12 (m, 2H), 9.04 (s, 1H).
1. (a) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Perkin
Trans.
I 1986, 701–710 and references cited therein.
(b) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc.,
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Nakayama, M.; Hayashi, S. J. Chem. Soc., Perkin Trans. 1
1979, 2652–2656. (d) Buchanan, M. S.; Connolly, J. D.;
Rycroft, D. S. Phytochemistry 1996, 43, 1245–1248.
(e) Asakawa, Y.; Tada, Y.; Hashimto, J. Phytochemistry
1994, 36, 1555–1556. (f) Asakawa, Y.; Lin, X.; Kondo, K.;
Fukuyama, Y. Phytochemistry 1991, 30, 4019–4024.
(g) Nagashima, F.; Nishioka, E.; Kameo, K.; Nakagawa, C.;
Asakawa, Y. Phytochemistry 1991, 30, 215–217.
To a stirred solution of crude aldehyde in diethylene glycol
(4 mL) was added hydrazine monohydrate (0.024 g,
0.48 mmol) and sodium hydroxide (0.355 g, 8.875 mmol)
at room temperature and mixture was stirred at 150 8C for
4 h and at 190 8C for additional 3 h. The reaction mixture
was diluted with water (25 mL) and extracted using diethyl
ether (15 mL!2). The combined organic layer was then
washed with water and brine solution, dried over anhydrous
sodium sulphate, filtered and concentrated under reduced
pressure. The product was purified by flash column
chromatography (pet. ether/EtOAc, 99:1 as eluent) to give
(12) (0.068 g, 73% for 2 steps) as colorless liquid. [a]2D5Z
C56 (cZ1.25, CHCl3). 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, JZ7.9 Hz,
1H), 7.14–7.18 (m, 2H). 13C NMR (CDCl3, 50 MHz) d 16.8
(CH3), 19.9 (CH2), 24.5 (CH3), 24.9 (CH3), 26.7, (CH3),
37.1 (CH2), 39.9 (CH2), 44.4 (C), 50.1 (C), 55.3 (CH3),
109.1 (CH), 125.3 (CH), 129.8 (CH), 139.4 (C), 155.7 (C).
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4.1.14. (C)-b-Herbertenol (17). BBr3 (1 M solution in
CH2Cl2, 0.251 g, w1 mL, 1 mmol) was added dropwise to
methyl ether 12 (0.045 g, 0.19 mmol) in dry CH2Cl2 (5 mL)
at K78 8C. 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 BBr3 was
quenched with saturated NaHCO3 (1 mL). The organic layer

S. P. Chavan et al. / Tetrahedron 61 (2005) 3873–3879
3879
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