A stereoselective total synthesis of (+)-α-herbertenol

Article abstract of DOI:10.1016/j.tet.2003.12.055

A stereoselective total synthesis of (+)-α-herbertenol starting from the allyl alcohol 12, readily available in three steps from the monoterpene (R)-limonene, is described. Claisen rearrangement of the aryl allyl ether 10 and concomitant cyclisation furnished a 5:3 mixture of the tricyclic compounds 13 and 14. Degradation of the isopropenyl group followed by cleavage of the central ring and functional group manipulation transformed 13 into (+)-α-herbertenol (1b).

Full text of DOI:10.1016/j.tet.2003.12.055

Tetrahedron 60 (2004) 2125–2130
A stereoselective total synthesis of (1)-a-herbertenol
*
A. Srikrishna, N. Chandrasekhar Babu and M. Srinivasa Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 10 October 2003; revised 25 November 2003; accepted 18 December 2003
Abstract—A stereoselective total synthesis of (þ)-a-herbertenol starting from the allyl alcohol 12, readily available in three steps from the
monoterpene (R)-limonene, is described. Claisen rearrangement of the aryl allyl ether 10 and concomitant cyclisation furnished a 5:3 mixture
of the tricyclic compounds 13 and 14. Degradation of the isopropenyl group followed by cleavage of the central ring and functional group
manipulation transformed 13 into (þ)-a-herbertenol (1b).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
activities.1,2 The dimeric herbertanes mastigophorenes A
and B 3a and 3b, isolated3 along with their isomers
mastigophorenes C and D and herbertenols from the
liverwort Mastigophora diclados, were shown to stimulate
nerve growth. Recently,1a Asakawa and co-workers
reported the isolation of seven new members of the
herbertane group herbertenelactol 2b, 1,13-herbertenediol
4, 1,14-herbertenediol 5, 1,15-herbertenediol 6, herberte-
nones A and B 7a,b and 12-methoxy-herbertenediol 8 along
with dimeric herbertanes mastigophorenes A–C, from the
Japanese liverwort Herberta sakuraii.
Herbertanes are a small group of sesquiterpenes, which are
considered as chemical markers for the liverworts belonging
to the genus Herbertus.1a Isolation of the first members of
the herbertane group herbertene 1a, a-herbertenol 1b,
b-herbertenol 1c, herbertenediol 1d, herbertenal 1e and
herbertenolide 2a from Herberta adunca was reported
earlier by Matsuo and co-workers.1b Subsequently,1c
Rycroft et al. reported the isolation of the aldehyde 1f and
the ester 1g from Herbertus aduncus. The phenolic
herbertanes, for example, 1b–d have been shown to possess
interesting biological properties such as growth inhibiting
activity, antifungal, antilipid peroxidation and neurotropic
The presence of two vicinal quaternary carbons on a
cyclopentane moiety and associated biological activities
Keywords: Herbertenediol; Mastigophorenes; Cyclopentane.
*
Corresponding author. Tel.: þ91-80-2932215; fax: þ91-80-3600683; e-mail address: ask@orgchem.iisc.ernet.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.055

2126
A. Srikrishna et al. / Tetrahedron 60 (2004) 2125–2130
made mastigophorenes and herbertenols interesting syn-
thetic targets of current interest. Until recently, unlike the
parent hydrocarbon, the phenolic herbertanes have received
very little attention from synthetic chemists despite their
interesting biological properties. However, the scenario has
been changed and significant synthetic activity is reported
since 1999.2,4–6 The first enantioselective synthesis of (2)-
a-herbertenol 1b was reported5a by Abad and co-workers in
1999. The first synthesis of mastigophorenes A and B 3a and
3b was achieved5b in 1999 via the phenolic coupling of
natural herbertenediol 1d. Almost at the same time,5c
Meyers and Degnan reported an enantioselective synthesis
of herbertenediol (2)-1d and its conversion to mastigo-
phorenes A and B (2)-3a and (2)-3b. In 2001, Fukuyama
and co-workers reported5f the enantioselective synthesis of
(2)-a-herbertenol 1b and its conversion to (2)-herber-
tenediol 1d and mastigophorenes 3a and 3b. Recently, Kita
and co-workers have developed6a an enantioselective
synthesis of herbertenediol 1d via rearrangement of an
epoxytosylate, and later extended6b the methodology for the
synthesis of a-herbertenol 1b. Herein we wish to report a
stereoselective total synthesis of (þ)-a-herbertenol starting
from the readily and abundantly available monoterpene (R)-
limonene 9 employing Claisen rearrangement as the key
reaction for the generation of the chiral quaternary carbon
atom.
Scheme 2. Reagents, conditions and yields: (a) p-cresol, PPh3, DIAD, THF,
room temperature, 10 h, 85%; (b) PhNMe2, sealed tube, 180 8C, 72 h, 65%;
(c) O3/O2, CH2Cl2–MeOH (5:1), 270 8C; Ac2O, NEt3, DMAP, C6H6,
reflux, 75%; (d) K2CO3, MeOH, room temperature. 4 h, 83%; (e) PCC,
NaOAc, CH2Cl2, room temperature, 2 h, 88%.
silver nitrate impregnated silica gel column chromato-
graphy (see Section 2). After creating the requisite new
chiral quaternary carbon atom, the original chiral centre was
disposed off via degradation of the isopropenyl group
employing a Criegee rearrangement.9 Thus, ozonolysis of
the compound 13 in methylene chloride-methanol followed
by treatment of the resulting methoxy-hydroperoxide with
acetic anyhydride, triethylamine and 4-dimethylamino-
pyridine (DMAP) in refluxing benzene generated the acetate
15 in 75% yield. Hydrolysis of the acetate group followed
by oxidation of the resultant alcohol with pyridinium
It was contemplated that Claisen rearrangement of the aryl
ether 10 generates methylenecyclopentane 11 containing
the requisite chiral quaternary carbon atom, which can be
further elaborated into a-herbertenol 1b (Scheme 1).
Visualising the isopropenyl group as a masked hydroxy
group, the allyl alcohol 12 was chosen as the appropriate
chiral starting material, which could be readily obtained7
from the abundantly available monoterpene (R)-limonene 9.
The synthetic sequence is depicted in Schemes 2 and 3. To
begin with, the allyl alcohol 12 was prepared from
R-limonene in three steps,7 viz. chemoselective ozonolysis
of the ring olefin followed by intramolecular aldol
condensation and regioselective reduction. The allyl alcohol
12 was then coupled with p-cresol under Mitsunobu
conditions.8 Thus, reaction of the allyl alcohol 12 with
p-cresol in the presence of triphenylphosphine and diiso-
propyl azodicarboxylate (DIAD) furnished the ether 10 in
85% yield. Thermal activation of the ether 10 in N,N-
dimethylaniline in a sealed tube at 180 8C generated, instead
of the phenol 11, a <5:3 mixture of the cyclised products 13
and 14, in 65% yield, which were separated by silica gel and
Scheme 3. Reagents, conditions and yields: (f) Li, liq. NH3, THF, 0.5 h
83%; (g) K2CO3, MeI, Me2CvO, room temperature, 4 h, 92%; (h) PCC,
silica gel, CH2Cl2, 85%; (i) NaI, MeI, DME, room temperature, 12 h, 72%;
(j) NH2NH2.H2O, digol, 125 8C, 3 h; KOH, 190 8C, 12 h, 72%; (k) BBr3,
CH2Cl2, 0 8C–room temperature, 2 h, 76%.
Scheme 1.

A. Srikrishna et al. / Tetrahedron 60 (2004) 2125–2130
2127
chlorochromate (PCC) in the presence of sodium acetate
transformed the acetate 15 into the ketone (2)-16
[a]2D5¼2290 (c 1.28, CHCl3). Quite expectedly, the
same sequence transformed the minor isomer 14 into
the enantiomeric ketone (þ)-16, [a]2D4¼þ320 (c 1.25,
CHCl3).
residue over a silica gel column using ethyl acetate–hexane
(1:20) as eluent furnished the allyl aryl ether 10 (2.7 g, 85%)
as colourless oil. [a]D25¼100 (c 1.03, CHCl3). IR (neat):
n
max/cm21 3070, 1644, 1510, 1235, 1009. 1H NMR
(300 MHz, CDCl3þCCl4): d 7.00 (2H, d, J¼7.2 Hz), 6.76
(2H, d, J¼7.2 Hz), 4.67 (2H, s), 4.48 and 4.23 (2H, 2£d,
J¼10.5 Hz), 3.51 (1H, m), 2.50–2.15 (2H, m), 2.26 (3H, s),
2.15–1.95 (1H, m), 1.78 (3H, s), 1.75–1.55 (1H, m), 1.62
(3H, s). 13C NMR (75 MHz, CDCl3þCCl4): d 157.2 (C),
147.5 (C), 139.9 (C), 132.5 (C), 129.7 (2 C, CH), 129.5 (C),
114.6 (2 C, CH), 110.9 (CH2), 63.1 (CH2), 54.8 (CH), 38.0
(CH2), 28.0 (CH2), 20.5 (CH3), 19.3 (CH3), 14.3 (CH3).
Mass: m/z 242 (Mþ, 2%), 241 (3), 199 (10), 149 (11), 135
(15), 134 (15), 121 (26), 119 (23), 108 (100), 107 (47), 93
(35), 91 (41). HRMS: m/z Calcd for C17H23O (Mþ1):
243.1749. Found: 243.1752.
Next attention was turned to the conversion of the ketone
(2)-16 into a-herbertenol 1b. It was contemplated that
reductive methylation of the keto ether 16, employing alkali
metal in liquid ammonia and methyl iodide, followed by
Wolff–Kishner reduction of the resulting phenolic ketone
17 would directly furnish 1b. However, all our attempts
(which include different experimental procedures of lithium
or sodium in liquid ammonia with and without proton
source; samarium iodide; zinc and acetic acid; etc.) to
convert the tricyclic compound 16 directly into the ketone
17 were unsuccessful, and reductive cleavage of the central
ring using lithium in liquid ammonia conditions furnished
only the diol 18, in 83% yield.10 Treatment of the diol 18
with potassium carbonate and methyl iodide followed by
oxidation of the resultant monomethyl ether 19 furnished
the cyclopentanone 20. The stereochemistry of the second-
ary methyl group in 20 was assigned as trans to aryl group
on the basis of the chemical shift of the secondary methyl
group (d 1.02 ppm) in the 1H NMR spectrum. Alkylation of
the ketone 20 with sodium hydride and methyl iodide in
dimethoxyethane (DME) generated the ketone 21, which on
Wolff–Kishner reduction furnished the methyl ether 22 of
a-herbertenol. Finally, boron tribromide mediated cleavage
of the methyl ether 22 furnished (þ)-a-herbertenol 1b,
[a]2D6¼þ52.9 (c 0.7, CHCl3) {lit.1b for (2)-1b, [a]D¼255}.
The methyl ether 22 and a-herbertenol exhibited spectro-
scopic data (IR, 1H and 13C NMR) identical to those
reported in the literature.
2.1.2. (3S,3aS,8bS)-cis-3-Isopropenyl-3a,7,8b-trimethyl-
2,3,3a,8b-tetrahydro-1H-cyclopenta-(b)benzofuran (13).
A solution of the allyl aryl ether 10 (2.2 g, 9.09 mmol) and
N,N-dimethylaniline (1.2 ml) was placed in a sealed tube
under N2 atmosphere and heated to 180 8C for 3 days in an
oil bath. The reaction mixture was then cooled and diluted
with hexane. It was stirred with 6 N HCl for 1 h and then
extracted with hexane (3£5 ml). The combined organic
layer was washed with brine and dried (Na2SO4). Evapor-
ation of the solvent and purification of the residue over a
silica gel column using benzene–hexane (1:20) as eluent
furnished a 5:3 mixture of cyclised products 13 and 14
(1.4 g, 65%) as oil. Further separation on a silver nitrate
impregnated silica gel column furnished 13 (885 mg, 41%)
as oil, and 14 (520 mg, 24%) as a colourless solid, which
was recrystallised from hexanes.
Major isomer 13: [a]2D6¼283.9 (c 1.18, CHCl3). IR (neat):
n
max/cm21 1644, 1609, 1245, 887, 808. 1H NMR (300 MHz,
In conclusion, we have developed a convenient method-
ology for the stereoselective synthesis of a-herbertenol 1b
starting from the readily available monoterpene (R)-
limonene. Since the natural a-herbertenol has already
been transformed5f into natural herbertenediol 1d and
mastigophorenes 3a and 3b, the present sequence provides
a convenient route for the synthesis of the optical antipodes
of these natural products. Currently, we are investigating the
extension of the methodology for the enantiospecific
synthesis of other herbertane and cuparene
sesquiterpenoids.
CDCl3þCCl4): d 6.85 (2H, brs), 6.58 (1H, d, J¼8.4 Hz),
4.88 (1H, s), 4.70 (1H, s), 2.64 (1H, dd, J¼9.0 and 9.0 Hz),
2.28 (3H, s), 2.15–1.85 (2H, m), 1.86 (3H, s), 1.70–1.55
(2H, m), 1.21 (3H, s), 1.16 (3H, s). 13C NMR (75 MHz,
CDCl3þCCl4): d 154.7 (C), 144.9 (C), 138.3 (C), 129.5 (C),
128.4 (CH), 123.8 (CH), 111.3 (CH2), 109.6 (CH), 98.4 (C),
56.2 (CH), 53.7 (C), 39.1 (CH2), 26.5 (CH2), 24.6 (CH3),
23.5 (CH3), 21.0 (CH3), 16.7 (CH3). Mass: m/z 242 (Mþ,
42%), 227 (19), 174 (15), 173 (10), 161 (39), 160 (100), 159
(65), 145 (23). HRMS: m/z Calcd for C17H22ONa (MþNa):
265.1568. Found: 265.1577.
Minor isomer 14: mp 122–123 8C (crystallised from
hexane). [a]2D5¼116.4 (c 1.40, CHCl3). IR (neat): nmax
/
2. Experimental
cm21 3071, 1640, 1611, 1262, 1137, 1062, 912, 889, 807.
1H NMR (300 MHz, CDCl3þCCl4): d 6.81 (1H, d,
J¼7.5 Hz), 6.79 (1H, s), 6.51 (1H, d, J¼7.5 Hz), 4.93
(1H, s), 4.80 (1H, s), 2.50–2.25 (2H, m), 2.26 (3H, s), 2.00–
1.90 (1H, m), 1.81 (3H, s), 1.65–1.50 (2H, m), 1.33 (3H, s),
1.32 (3H, s). 13C NMR (75 MHz, CDCl3þCCl4): d 156.7
(C), 144.4 (C), 135.6 (C), 129.1 (C), 128.5 (CH), 123.4
(CH), 113.7 (CH2), 108.3 (CH), 98.9 (C), 58.7 (CH), 54.3
(C), 42.4 (CH2), 27.7 (CH2), 23.7 (CH3), 22.1 (CH3), 21.0
(CH3), 20.6 (CH3). Mass: m/z 242 (Mþ, 37%), 227 (18), 174
(18), 161 (47), 160 (100), 159 (72), 145 (25), 135 (16).
HRMS: m/z Calcd for C17H23O (Mþ1): 243.1749. Found:
243.1758.
2.1. Data for compounds
2.1.1. (1)-((5S)-5-Isopropenyl-2-methylcyclopent-1-
enyl)methyl 4-methylphenyl ether (10). To a magnetically
stirred solution of triphenylphosphine (4.12 g, 15.8 mmol)
in dry THF (4 ml) was added DIAD (2.84 ml, 14.46 mmol)
and stirred for 15 min at room temperature. A solution of the
allyl alcohol7 12 (2.0 g, 13.15 mmol) and p-cresol (1.42 g,
13.15 mmol) in dry THF (2 ml) was added to the reaction
mixture and stirred for 10 h at room temperature. It was then
diluted with CH2Cl2 (15 ml), washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of the

2128
A. Srikrishna et al. / Tetrahedron 60 (2004) 2125–2130
2.1.3. (2)-(3R,3aR,8bS)-cis-3a,7,8b-Trimethyl-2,3,3a,8b-
tetrahydro-1H-cyclopenta(b)benzofuran-3-yl acetate
(15). Pre-cooled dry ozone in oxygen gas was passed
through a cold (270 8C) suspension of the ether 13 (400 mg,
1.65 mmol) and NaHCO3 (5 mg) in 4:1 CH2Cl2–MeOH
(5 ml) until reaction mixture turns blue and then the excess
ozone was flushed off with oxygen. The solvent was
evaporated in vacuo and the residue was taken in dry
benzene (3 ml). Acetic anhydride (2.33 ml, 24.75 mmol),
triethylamine (2.3 ml, 16.5 mmol) and a catalytic amount of
DMAP (5 mg) were added to the reaction mixture and
refluxed for 4 h. It was then cooled, diluted with water and
extracted with ether (3£4 ml). The ether extract was washed
with 3 N aqueous HCl and brine, and dried (Na2SO4).
Evaporation of the solvent under reduced pressure and
purification of the residue over a silica gel column using
ethyl acetate–hexane (1:10) as eluent furnished the acetate
15 (320 mg, 75%) as oil. [a]2D3¼258.6 (c 2.54, CHCl3). IR
J¼12.3, 12.3, 7.2 Hz), 1.35 (3H, s), 1.34 (3H, s). 13C NMR
(75 MHz, CDCl3þCCl4): d 215.6 (C), 155.9 (C), 133.2 (C),
130.8 (C), 129.4 (CH), 123.3 (CH), 109.6 (CH), 91.4 (C),
51.3 (C), 35.6 (CH2), 32.4 (CH2), 23.5 (CH3), 21.0 (CH3),
14.6 (CH3). Mass: m/z 216 (Mþ, 20%), 202 (13), 187 (19),
173 (17), 160 (100), 159 (59), 145 (34), 115 (13). HRMS:
m/z Calcd for C14H16O2Na (MþNa): 239.1048. Found:
239.1045.
2.1.5. (2)-2-[(1R,2S,3R)-3-Hydroxy-1,2-dimethylcyclo-
pentyl]-4-methylphenol (18). To a magnetically stirred,
freshly distilled (over sodium and ferric chloride) ammonia
(100 ml) in a two necked flask, equipped with Dewar
condenser, was added freshly cut lithium (25 mg,
3.68 mmol) followed by a solution of the ketone 16
(200 mg, 0.92 mmol) in anhydrous THF (3 ml). The
resulting blue coloured solution was stirred for 15 min. at
233 8C and then the reaction was quenched with solid
NH4Cl. After evaporation of ammonia, the residue was
taken in water (5 ml) and extracted with ether (3£5 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
(1:5) as eluent, furnished the diol 18 (168 mg, 83%) which
was recrystallised from ether. Mp 72–74 8C. [a]2D5¼223.6
(c 0.93, CHCl3). IR (neat): nmax/cm21 3349, 1608, 1251,
1213, 1124, 1047, 1000, 813. 1H NMR (300 MHz, CDCl3þ
CCl4): d 6.95 (1H, s), 6.83 (1H, d, J¼8.1 Hz), 6.58 (1H, d,
J¼8.1 Hz), 3.97 (1H, q, J¼6.5 Hz), 2.55–2.40 (2H, m),
2.26 (3H, s), 2.15–1.90 (1H, m), 1.80–1.55 (3H, m), 1.23
(3H, s), 0.99 (3H, d, J¼6.9 Hz). 13C NMR (75 MHz,
CDCl3þCCl4): d 152.0 (C), 134.8 (C), 128.9 (C), 127.8
(CH), 127.5 (CH), 117.0 (CH), 81.0 (CH), 49.2 (CH), 45.5
(C), 36.9 (CH2), 33.1 (CH2), 22.5 (CH3), 21.0 (CH3), 13.5
(CH3). Mass: m/z 220 (Mþ, 20%), 202 (60), 187 (100), 173
(40), 159 (80), 147 (40), 133 (20), 118 (40), 105 (20).
HRMS: m/z Calcd for (M-OH) C14H19O: 203.1436. Found:
203.1436.
1
(neat): nmax/cm21 1742, 1610, 1237, 1072, 810. H NMR
(300 MHz, CDCl3þCCl4): d 6.83 (1H, d, J¼7.8 Hz), 6.80
(1H, s), 6.53 (1H, d, J¼8.1 Hz), 5.26–5.18 (1H, m), 2.26
(3H, s), 2.07 (3H, s), 2.00–1.55 (4H, m), 1.36 (3H, s), 1.30
(3H, s). 13C NMR (75 MHz, CDCl3þCCl4): d 169.3 (C),
155.5 (C), 135.4 (C), 129.7 (C), 128.8 (CH), 123.5 (CH),
109.0 (CH), 98.7 (C), 81.8 (CH), 53.5 (C), 41.3 (CH2),
29.0 (CH2), 22.9 (CH3), 21.1 (CH3), 21.0 (CH3), 17.0
(CH3). Mass: m/z 260 (Mþ, 30%), 218 (25), 203 (100), 173
(14), 161 (18), 160 (29), 159 (48), 145 (29). HRMS: m/z
Calcd for C16H20O3Na (MþNa): 283.1310. Found:
283.1314.
2.1.4. (2)-(3R,8bS)-cis-3a,7,8b-Trimethyl-2,3,3a,8b-
tetrahydro-1H-cyclopenta[b]benzofuran-3-one (16). To
a magnetically stirred solution of the acetate 15 (300 mg,
1.15 mmol) in methanol (4 ml) was added K2CO3 (317 mg,
2.30 mmol) and stirred at room temperature for 2 h. Water
(10 ml) was then added to the reaction mixture and
extracted with CH2Cl2 (3£4 ml). The combined CH2Cl2
extract was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue
over a silica gel column using ethyl acetate–hexane (1:5) as
eluent furnished the alcohol (208 mg, 83%) as oil,
{[a]2D5¼234.3 (c 4.4, CHCl3). IR (neat): nmax/cm21 3351,
1607, 1264, 1241, 1024, 809. 1H NMR (300 MHz, CDCl3þ
CCl4): d 6.82 (1H, d, J¼7.5 Hz), 6.81 (1H, s), 6.51 (1H, d,
J¼7.5 Hz), 4.16 (1H, brs), 2.26 (3H, s), 2.06 (1H, ddd,
J¼12.0, 12.0, 6.9 Hz), 1.86 (1H, ddd, J¼12.0, 6.9, 2.3 Hz),
1.80–1.50 (3H, m), 1.37 (3H, s), 1.35 (3H, s). 13C NMR
(75 MHz, CDCl3þCCl4): d 155.5 (C), 136.1 (C), 129.6 (C),
128.5 (CH), 123.6 (CH), 108.7 (CH), 99.6 (C), 80.2 (CH),
53.0 (C), 41.0 (CH2), 31.1 (CH2), 23.3 (CH3), 21.0 (CH3),
16.8 (CH3)}, which was taken in 2 ml of CH2Cl2 and added
to a magnetically stirred suspension of PCC (490 mg,
2.30 mmol) and sodium acetate (490 mg) in CH2Cl2 (2 ml).
The reaction mixture was stirred at room temperature for
2 h, filtered through a silica gel column, and the column was
eluted with more CH2Cl2. The solvent was evaporated to
furnish the ketone 16 (217 mg, 88%) which was
recrystallised from ether. Mp 96–98 8C. [a]2D5¼290.6 (c
1.28, CHCl3). IR (neat): nmax/cm21 1744, 1608, 1233, 1056,
2.1.6. (2)-(1R,2S,3R)-2,3-Dimethyl-3-(2-methoxy-5-
methylphenyl)cyclopentanol (19). To a magnetically
stirred solution of the diol 18 (150 mg, 0.68 mmol) in
acetone (4 ml) was added K2CO3 (188 mg, 1.36 mmol) and
MeI (0.43 ml, 1.36 mmol) and stirred at room temperature
for 4 h. Water (5 ml) was then added to the reaction mixture
and extracted with CH2Cl2 (3£4 ml). The combined CH2Cl2
extract was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the residue
over a silica gel column using ethyl acetate–hexane (1:10)
as eluent furnished the methyl ether 19 (145 mg, 92%) as
oil. [a]2D4¼236.1 (c 0.36, CHCl3). IR (neat): nmax/cm21
1
3368, 1288, 1239, 1052, 1032, 807. H NMR (300 MHz,
CDCl3þCCl4): d 6.95 (1H, s), 6.92 (1H, d, J¼8.1 Hz), 6.72
(1H, d, J¼8.1 Hz), 3.88 (1H, q, J¼7.2 Hz), 3.80 (3H, s),
2.40–2.00 (3H, m), 2.28 (3H, s), 1.82 (1H, ddd, J¼12.5, 8.0,
8.0 Hz), 1.75–1.50 (2H, m), 1.18 (3H, s), 1.03 (3H, d,
J¼7.2 Hz). 13C NMR (75 MHz, CDCl3þCCl4): d 156.0 (C),
137.5 (C), 129.1 (C), 127.5 (CH), 127.2 (CH), 111.6 (CH),
80.0 (CH), 55.1 (CH3), 49.2 (CH), 45.7 (C), 37.0 (CH2),
33.0 (CH2), 22.7 (CH3), 21.0 (CH3), 13.2 (CH3). Mass: m/z
234 (Mþ, 17%), 165 (100), 149 (15), 147 (23), 145 (15), 135
(15), 119 (18), 105 (11). HRMS: m/z Calcd for C15H22O2Na
(MþNa): 257.1517. Found: 257.1512.
1
819. H NMR (300 MHz, CDCl3þCCl4): d 6.90 (2H, brs),
6.23 (1H, d, J¼8.4 Hz), 2.40–2.20 (2H, m), 2.28 (3H, s),
2.03 (1H, ddd, J¼18.0, 12.3, 9.0 Hz), 1.85 (1H, ddd,

A. Srikrishna et al. / Tetrahedron 60 (2004) 2125–2130
2129
2.1.7. (1)-(2S,3R)-2,3-Dimethyl-3-(2-methoxy-5-methyl-
phenyl)cyclopentanone (20). To a magnetically stirred
suspension of PCC (258 mg, 1.20 mmol) and silica gel
(258 mg) in 2 ml dry CH2Cl2 was added a solution of the
alcohol 19 (140 mg, 0.60 mmol) in 2 ml dry CH2Cl2 and
stirred vigorously for 2 h at room temperature. The reaction
mixture was then filtered through a small silica gel column,
and the column eluted with more CH2Cl2. Evaporation of
the solvent furnished the ketone 20 (118 mg, 85%) as oil.
[a]2D2¼31.2 (c 1.25, CHCl3). IR (neat): nmax/cm21 3030,
1738, 1610, 1234, 1071, 808. 1H NMR (300 MHz, CDCl3þ
CCl4): d 6.98 (1H, d, J¼8.1 Hz), 6.96 (1H, s), 6.77 (1H, d,
J¼8.1 Hz), 3.82 (3H, s), 3.02 (1H, q, J¼6.9 Hz), 2.50–2.10
(4H, m), 2.30 (3H, s), 1.22 (3H, s), 1.02 (3H, d, J¼6.9 Hz).
13C NMR (75 MHz, CDCl3þCCl4): d 219.9 (C), 156.2 (C),
134.6 (C), 129.4 (C), 127.9 (2 C, CH), 111.7 (CH), 55.1
(CH3), 51.8 (CH), 45.9 (C), 35.0 (CH2), 32.8 (CH2), 21.0
(CH3), 20.0 (CH3), 9.5 (CH3). Mass: m/z 232 (Mþ, 79%),
217 (51), 199 (22), 175 (100), 161 (40), 149 (43), 147 (50),
145 (35), 115 (31), 105 (39), 91 (40). HRMS: m/z Calcd for
C15H21O2 (Mþ1): 233.1541. Found: 233.1547.
(300 MHz, CDCl3þCCl4): d 7.04 (1H, s), 6.88 (1H, dd,
J¼8.1, 1.8 Hz), 6.68 (1H, d, J¼7.8 Hz), 3.74 (3H, s), 2.60–
2.45 (1H, m), 2.26 (3H, s), 1.80–1.40 (5H, m), 1.33 (3H, s),
1.13 (3H, s), 0.66 (3H, s). 13C NMR (75 MHz, CDCl3þ
CCl4): d 156.7 (C), 135.8 (C), 129.6 (CH), 128.7 (C), 127.1
(CH), 111.5 (CH), 54.8 (CH3), 51.3 (C), 44.3 (C), 42.3
(CH2), 40.0 (CH2), 27.9 (CH3), 26.2 (CH3), 23.2 (CH3), 21.1
(CH3), 20.7 (CH2). Mass: m/z 233 (Mþ1, 12%), 232 (74),
175 (30), 162 (63), 161 (29), 150 (30), 149 (100), 147 (70),
145 (31), 135 (34), 119 (29), 105 (22), 91 (28).
2.1.10. (1)-4-Methyl-2-(R-1,2,2-trimethylcyclopentyl)-
phenol (a-herbertenol 1b). A solution of BBr3 (1 M in
CH2Cl2, 0.04 ml, 0.04 mmol) was added drop wise to a
solution of the ether 22 (5 mg, 0.02 mmol) in CH2Cl2
(1.5 ml) at 0 8C. The reaction mixture was stirred for 2 h at
room temperature, then quenched with saturated aqueous
NaHCO3 solution and extracted with CH2Cl2 (3£3 ml). The
combined organic layer was washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of the
residue over a silica gel column using ethyl acetate–hexane
(1:5) as eluent furnished ent-a-herbertenol 1b (3.5 mg,
2.1.8. (1)-(3S)-2,2,3-Trimethyl-3-(2-methoxy-5-methyl-
phenyl)cyclopentanone (21). To a magnetically stirred
suspension of NaH (2.8 mg, 60% dispersion in oil,
0.07 mmol, washed with dry hexane) in DME (1 ml) was
added a solution of the ketone 20 (20 mg, 0.086 mmol) in
DME (1 ml), and stirred for 0.5 h at room temperature.
Methyl iodide (0.05 ml) was then added to the reaction
mixture and stirred for 12 h. It was then quenched with
water (2 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 over a silica gel column using ethyl acetate–hexane
(1:20) as eluent furnished the ketone 21 (10 mg, 72%, based
on the starting material consumed) as oil.5i [a]D26¼58.9 (c
0.9, CHCl3). IR (neat): nmax/cm21 1738, 1501, 1244, 1029,
76%) as oil. [a]D26¼52.8 (c 0.7, CHCl3). IR (neat): nmax
/
cm21 3531, 1506, 1251, 1165, 808. H NMR (300 MHz,
CDCl3þCCl4): d 7.03 (1H, s), 6.80 (1H, d, J¼8.1 Hz), 6.50
(1H, d, J¼8.1 Hz), 4.51 (1H, s), 2.65–2.45 (1H, m), 2.25
(3H, s), 1.90–1.30 (5H, m), 1.40 (3H, s), 1.17 (3H, s), 0.75
(3H, s). 13C NMR (75 MHz, CDCl3þCCl4): d 152.3 (C),
132.9 (C), 130.1 (CH), 128.8 (C), 127.3 (CH), 116.7 (CH),
51.1 (C), 44.8 (C), 41.5 (CH2), 39.6 (CH2), 27.3 (CH3), 25.8
(CH3), 23.1 (CH3), 21.1 (CH3), 20.5 (CH2). Mass: m/z 218
(Mþ, 32%), 161 (23), 148 (81), 147 (38), 135 (83), 121 (36),
105 (22).
1
Acknowledgements
1
807. H NMR (300 MHz, CDCl3þCCl4): d 7.08 (1H, d,
Financial support from the Council of Scientific and
Industrial Research, New Delhi is gratefully acknowledged.
J¼1.8 Hz), 6.98 (1H, d, J¼8.1 Hz), 6.72 (1H, d, J¼8.1 Hz),
3.73 (3H, s), 2.60–2.35 (3H, m), 2.30 (3H, s), 2.15–1.85
(1H, m), 1.38 (3H, s), 1.21 (3H, s), 0.64 (3H, s). 13C NMR
(75 MHz, CDCl3þCCl4): d 222.1 (C), 156.0 (C), 134.5 (C),
129.1 (C), 128.6 (CH), 127.7 (CH), 111.0 (CH), 54.2 (CH3),
52.3 (C), 48.7 (C), 34.5 (CH2), 32.8 (CH2), 23.5 (CH3), 22.0
(CH3), 21.9 (CH3), 21.0 (CH3). Mass: m/z 246 (Mþ, 74%),
231 (16), 213 (14), 197 (14), 175 (100), 161 (32), 147 (45),
115 (33), 105 (36), 91 (46). HRMS: m/z Calcd for
C16H22O2Na (MþNa): 269.1517; Found: 269.1536.
References and notes
1. (a) Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y.
Phytochemistry 2000, 55, 247. (b) Matsuo, A.; Yuki, S.;
Nakayama, M. J. Chem. Soc., Perkin Trans. 1 1986, 701.
(c) Buchanan, M. S.; Connolly, J. D.; Rycroft, D. S.
Phytochemistry 1996, 43, 1245.
2.1.9. (1)-(R)-1-(2-Methoxy-5-methylphenyl)-1,2,2-tri-
methylcyclopentane (22). A solution of the ketone 21
(5 mg, 0.02 mmol), potassium hydroxide (11 mg,
0.2 mmol) and hydrazine hydrate (0.2 ml, 0.4 mmol) in
diethylene glycol (2 ml) was taken in a sealed tube and
heated to 125 8C for 3 h and then to 190 8C for 12 h. The
reaction mixture was then cooled, acidified with 3 N
aqueous HCl (5 ml) and extracted with CH2Cl2 (3£3 ml).
The combined CH2Cl2 extract was washed with brine and
dried (Na2SO4). Evaporation of the solvent and purification
of the residue over silica gel column using ethyl acetate–
hexane (1:20) as eluent furnished the deoxygenated product
22 (3.5 mg, 72%) as oil.6b [a]D26¼41.0 (c 1.0, CHCl3). IR
2. Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett.
1996, 37, 1261.
3. Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1
1991, 2737.
4. Racemic synthesis of phenolic herbertanes: (a) Eicher, T.;
Servet, F.; Speicher, A. Synthesis 1996, 863. (b) Pal, A.;
Gupta, P. D.; Roy, A.; Mukherjee, D. Tetrahedron Lett. 1999,
40, 4733. (c) Harrowven, D. C.; Hannam, J. C. Tetrahedron
1999, 55, 9333. (d) Gupta, P. D.; Pal, A.; Roy, A.; Mukherjee,
D. Tetrahedron Lett. 2000, 41, 7563. (e) Srikrishna, A.; Rao,
M. S. Tetrahedron Lett. 2001, 42, 5781. (f) Fukuyama, Y.;
Yuasa, H.; Tonoi, Y.; Harada, K.; Wada, M.; Asakawa, Y.;
Hashimoto, T. Tetrahedron 2001, 57, 9299. (g) Abad, A.;
Agullo, C.; Cunat, A. C.; Jimenez, D.; Perni, R. H.
1
(neat): nmax/cm21 1607, 1241, 1179, 1034, 806. H NMR

2130
A. Srikrishna et al. / Tetrahedron 60 (2004) 2125–2130
Tetrahedron 2001, 9727–9735. (h) Srikrishna, A.; Rao, M. S.
Okazaki, H.; Mitsumoto, Y. Tetrahedron 2001, 57, 7127.
(g) Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P.;
Peters, K.; Peters, E. M. Synthesis 2001, 155. (h) Bringmann,
G.; Pabst, T.; Henschel, P.; Michel, M. Tetrahedron 2001, 57,
1269.
Tetrahedron Lett. 2002, 43, 151. (i) Srikrishna, A.; Rao, M. S.
Synlett 2002, 340. (j) Paul, T.; Pal, A.; Gupta, P. D.;
Mukherjee, D. Tetrahedron Lett. 2003, 44, 737. (k) Srikrishna,
A.; Satyanarayana, G. Tetrahedron Lett. 2003, 44, 1027.
(l) Chavan, S. P.; Kharul, R. K.; Kale, R. R.; Khobragade, D. A.
Tetrahedron 2003, 59, 2737.
6. (a) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh,
J. K.; Fujioka, H. Tetrahedron Lett. 2003, 44, 411. (b) Kita, Y.;
Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, J. K.; Fujioka,
H. J. Org. Chem. 2003, 68, 5917.
5. Enantioselective synthesis of phenolic herbertanes and
´
mastigophorones: (a) Abad, A.; Agullo, C.; Cun˜at, A. C.;
Perni, R. H. J. Org. Chem. 1999, 64, 1741. (b) Bringmann, G.;
Pabst, T.; Rycroft, D. S.; Connolly, J. D. Tetrahedron Lett.
1999, 40, 483. (c) Degnan, A. P.; Meyers, A. I. J. Am. Chem.
Soc. 1999, 121, 2762. (d) Bringmann, G.; Pabst, T.; Henschel,
P.; Kraus, J.; Peters, K.; Peters, E. M.; Rycroft, D. S.;
Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127. (e) Abad,
´
A.; Agullo, C.; Cun˜at, A. C.; Perni, R. H. Tetrahedron:
Asymmetry 2000, 11, 1607. (f) Fukuyama, Y.; Matsumoto, K.;
Tonoi, Y.; Yokoyama, R.; Takahashi, H.; Minami, H.;
7. Srikrishna, A.; Babu, N. C. Tetrahedron Lett. 2001, 42, 4913.
For a five step conversion of limonene to the allyl alcohol 12
see: Wolinsky, J.; Slabaugh, M. R.; Gibson, T. J. Org. Chem.
1964, 29, 3740.
8. Hughes, D. L. Org. React. 1992, 42, 335.
9. Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24,
2363.
10. Despite careful experimentation, we were not able to stop the
reaction to furnish the ketone, and it led only to the diol 18.