The first total synthesis of (±)-γ-herbertenol, a herbertene isolated from a non-herbertus source

Article abstract of DOI:10.1055/s-2006-950355

The structure of the aromatic sesquiterpene, (±)-γ- herbertenol, the first herbertane to be isolated from a non-herbertus source, was confirmed by a total synthesis, employing a Claisen rearrangement and ring-closing metathesis. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-2006-950355

PAPER
65
The First Total Synthesis of ( )-g-Herbertenol, a Herbertene Isolated from a
Non-Herbertus Source
First Total
S
ynthes
.
is of
(
)-
g
-H
S
erbertenol rikrishna,* P. C. Ravikumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax +91(80)23600529; E-mail: ask@orgchem.iisc.ernet.in
Received 7 August 2006; revised 14 September 2006
15
14
Abstract: The structure of the aromatic sesquiterpene, ( )-g-her-
bertenol, the first herbertane to be isolated from a non-herbertus
source, was confirmed by a total synthesis, employing a Claisen re-
arrangement and ring-closing metathesis.
1
7
3
9
5
13
1 (cuparene)
2 (herbertene)
Key words: natural products, total synthesis, rearrangement, ring
closure, metathesis
X
O
Y
R
X
OH
OH
OH
Z
Liverworts from the genus Herbertus contain herbertane
sesquiterpenoids, which are considered to be chemical
markers of the genus.1 The herbertane group is a small
group of aromatic sesquiterpenes, isomeric to cuparanes,
containing a sterically crowded 1-aryl-1,2,2-trimethylcy-
clopentane carbon framework incorporating two vicinal
quaternary carbon atoms on a cyclopentane ring. Though
cuparene (1), isomeric to herbertane, has been known
since 1958,2 the herbertane family of sesquiterpenes was
only reported in the 1980s. The first member of the family
to be identified, herbertene (2), was isolated in 1981 by
Matsuo and coworkers from an ethyl acetate extract of the
liverwort Herberta adunca (Dicks) S. Gray, belonging to
the family herbertaceae.3 Subsequently, several other her-
bertenoids 3–16, mostly phenolic herbertanes, were iso-
lated from a variety of Herbertus sources (Figure 1). The
herbertane sesquiterpenes (mainly the phenolic herber-
tanes) possess interesting biological properties, such as
growth-inhibiting activity and antilipid peroxidation ac-
tivity.1,4
11
9 X = O
10 X = H, OH
3 R = Me, X = OH, Y = Z = H
4 R = Me, X = Y = H, Z = OH
5 R = Me, X = Y = OH, Z = H
6 R = CHO, X = OH, Y = Z = H
7 R = CHO, X = Y = OH, Z = H
OH
8 R = COOEt, X = Y = OH, Z = H
12
HO
OH
O
OH
Me
OH
OH
MeOH2C
13, 14
15
16
Figure 1
cal properties associated with the phenolic herbertanes,
made herbertenoids interesting and challenging synthetic
targets. Prior to 1999, only three reports appeared in the
literature on the synthesis of phenolic herbertanes. How-
ever, since then, nearly forty reports have described the
synthesis of phenolic herbertanes, making it a topic of
contemporary interest.6 We addressed the total synthesis
of g-herbertenol [( )-18] in order to confirm the structure
of the natural product. Herein, we wish to report the first
total synthesis of 18 via a combination of Claisen rear-
rangement and ring-closing metathesis (RCM) reac-
tions.6b
Contrary to the assumption that herbertanes are chemical
markers of liverwort belonging to the genus Herbertus,1
Becker et al.5 recently reported the isolation of two new
herbertanes, herbertene-1,12-diol (17) and g-herbertenol
(18) (Figure 2), along with aromadendranes and a-her-
bertenol (3) from the liverwort Tylimanthus renifolius.
For years, it was believed that herbertanes are restricted to
Herbertus species and their potential as a chemical marker
of these genera has been discussed. The occurrence of her-
bertene sesquiterpenes in T. renifolius is remarkable in
that it questions the validity of this hypothesis.
A retrosynthetic analysis is depicted in Scheme 1. It was
anticipated that g-herbertenol (18) could be obtained from
the enone 19, containing the requisite two quaternary car-
The presence of a sterically crowded 1-aryl-1,2,2-trimeth-
ylcyclopentane carbon framework, the difficulty associat-
ed with the construction of vicinal quaternary carbon
atoms on a cyclopentane ring and the significant biologi-
OH
OH
17
SYNTHESIS 2007, No. 1, pp 0065–0074
Advanced online publication: 02.11.2006
x
x
.
x
x
.2
0
0
6
OH
18
Figure 2
DOI: 10.1055/s-2006-950355; Art ID: P09606SS
© Georg Thieme Verlag Stuttgart · New York

66
A. Srikrishna, P. C. Ravikumar
PAPER
O
OH
OH
OMe
OMe
18
19
20
O
O
OH
H
OMe
OMe
OMe
22
23
21
Scheme 1
bons, which in turn could be obtained from the hydroxy-
diene 20, via an RCM reaction.7 The hydroxydiene 20
could be prepared from the aldehyde 21, which in turn
could be obtained from the acetophenone 22 via the Clais-
en rearrangement of the cinnamyl alcohol 23.
O
X
a
d,c
85%
83%
OMe
OMe
OMe
25 X = CH2Br
26 X = CH2OH
27 X = CHO
b, 80%
c, 94%
24
22
Since no reports on the synthesis of 3-methoxy-5-methyl-
acetophenone 22 could be found in the literature, we first
focused our attention on the synthesis of this starting ma-
terial (Scheme 2). Reaction of the anisole 24 with one
equivalent of N-bromosuccinimide (NBS) and a catalytic
amount of benzoyl peroxide in refluxing carbon tetrachlo-
ride for one hour, furnished 3-methoxy-5-methylbenzyl
bromide 25 in 83% yield. Solvolysis of the benzyl bro-
mide 25 in refluxing aqueous acetone, in the presence of
sodium bicarbonate, furnished the benzyl alcohol 26 in
80% yield. Oxidation of this alcohol with pyridinium
chlorochromate (PCC) and silica gel in dichloromethane
furnished the aldehyde 27 in 94% yield.8 Grignard reac-
tion of the aldehyde 27 with methylmagnesium iodide,
followed by oxidation of the resultant benzyl alcohol 28
with PCC and silica gel, furnished the acetophenone 22,
the structure of which was established from spectral data.
Horner–Wadsworth–Emmons reaction of the acetophen-
one 22 with sodium hydride and triethyl phosphonoace-
tate in refluxing THF, furnished a 12:1 E:Z mixture of the
cinnamate 29, which, on regioselective reduction at low
temperature (–50 °C) with lithium aluminium hydride
(LAH), gave an E/Z-mixture of the allyl alcohol 23.
e, 90%
X
g
+
CHO
64%
CHO
OMe
OMe
OMe
29 X = COOEt
23 X = CH2OH
(1:4)
f, 84%
21
30
Scheme 2 Reagents and conditions: (a) NBS, (PhCO2)2, CCl4; (b)
H2O, Me2CO; (c) PCC, silica gel, CH2Cl2; (d) MeMgI, Et2O; (e)
(EtO)2P(O)CH2CO2Et, NaH, THF; (f) LAH, Et2O; (g) CH2=CHOEt,
Hg(OAc)2, D.
ular ene reaction of the enol tautomer 31 of the aldehyde
21, generates the cyclopropyl aldehyde 32. A retroene re-
action (or 1,5 hydrogen transfer) of the cyclopropyl alde-
hyde 32 would then generate either the starting aldehyde
21 or the rearranged aldehyde 30 via the cleavage of the
cyclopropane bonds ‘a’ or ‘b’, respectively.
H
O
Attention was then focused on the creation of the first qua-
ternary carbon atom. Thomas’ one-pot variant9 of the
Claisen rearrangement was explored for the direct conver-
sion of the allyl alcohol 23 into the g,d-unsaturated alde-
hyde 21. Thus, reaction of the allyl alcohol 23 and ethyl
vinyl ether, in the presence of a catalytic amount of mer-
curic acetate at 175 °C in a sealed tube, furnished an in-
separable ~7:2 mixture of the g,d-unsaturated aldehyde 21
and the abnormal Claisen rearrangement product 30 in
64% overall yield. Structures of the two aldehydes 21 and
21
30
a
O
a
b
b
ene
21
H
reaction
OMe
31
OMe
32
Scheme 3
In order to overcome the problems associated with the iso-
lation and low yield of the desired aldehyde 21, an alter-
native three-step sequence via Johnson’s orthoester
variant11 of the Claisen rearrangement was investigated
(Scheme 4). Thus, reaction of the allyl alcohol 23 with tri-
1
30 were assigned based on the H NMR spectrum of the
mixture. The formation of the abnormal Claisen rear-
rangement product 30 could be explained by an enolene
rearrangement as depicted in Scheme 3.10 An intramolec-
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of ( )-g-Herbertenol
67
OH
OH
X
a
d
81%
82%
OMe
OMe
OMe
23
20
33 X = COOEt
34 X = CH2OH
21 X = CHO
b, 98%
c, 77%
e
90%
f
O
c
O
OH
78%
91%
OMe
99%
OMe
OMe
19
36
35
g
S
h
i
O
S
79%
OMe
100%
OMe
37
OMe
38
39
Scheme 4 Reagents and conditions: (a) MeC(OEt)3, EtCO2H, D; (b) LAH, Et2O; (c) PCC, silica gel, CH2Cl2; (d) CH2=CHMgBr, THF; (e)
PhCH=Ru(PCy3)2Cl2, CH2Cl2; (f) NaH, THF, DMF, MeI; (g) H2, 10% Pd/C, EtOH; (h) I2, (CH2SH)2, CH2Cl2; (i) Raney Ni, EtOH.
ethyl orthoacetate, in the presence of a catalytic amount of An alternative strategy was also investigated for the syn-
propionic acid in a sealed tube at 180 °C for 48 hours, thesis of g-herbertenol methyl ether 39 starting from the
generated the g,d-unsaturated ester 33 in 81% yield. Re- g,d-unsaturated ester 33 (Scheme 5). It was thought that g-
duction of this ester with LAH in ether at 0 °C, furnished herbertenol methyl ether 39 could be prepared via an
the primary alcohol 34 in 98% yield, which on oxidation RCM reaction of the diene ester 40. Thus, generation of
with PCC and silica gel furnished the aldehyde 21 in 77% the lithium enolate of the ester 33 with LDA in THF at
yield. Grignard reaction of the aldehyde 21 with vinyl- –70 °C, followed by alkylation with allyl bromide, gener-
magnesium bromide in dry THF at room temperature gen- ated a 9:4 diastereomeric mixture of the ester 40 in 83%
erated, as expected, a 1:1 epimeric mixture of the yield. Reaction of the diene ester 40 with 5 mol% of
hydroxydiene 20 in 82% yield. Treatment of 20 with 5 Grubbs’ first-generation catalyst in anhydrous dichlo-
mol%
of
Grubbs’
first-generation
catalyst romethane at room temperature for five hours furnished
[PhCH=Ru(PCy3)2Cl2] in anhydrous dichloromethane at the ester 41 in near quantitative yield. Generation of the
room temperature for one hour furnished a 1:1 diastereo- lithium enolate of the ester 41 with LDA in THF and hexa-
meric mixture of the cyclopentenol 35 in 90% yield. Oxi- methylphosphoramide (HMPA) at –30 °C, followed by
dation of 35 with PCC and anhydrous sodium acetate treatment with methyl iodide, furnished a 4:1 diastereo-
furnished the cyclopentenone 36 in 91% yield. Reaction meric mixture of the alkylated product 42 in 68% yield.
of the cyclopentenone 36 with sodium hydride and methyl Catalytic hydrogenation using 10% Pd/C transformed the
iodide in dry tetrahydrofuran and N,N-dimethylform- ester 42 in to the saturated ester 43 in 99% yield. Reduc-
amide at room temperature generated the enone 19, con- tion of the ester 43 with LAH in ether at 0 °C, furnished a
taining the complete carbon framework of herbertanes, in 4:1 mixture of the primary alcohol 44, which on oxidation
78% yield. Hydrogenation of the enone 19, using 10% with PCC and silica gel furnished the aldehyde 45. Treat-
palladium over carbon as the catalyst at atmospheric hy- ment of the aldehyde 45 with hydrazine hydrate in digol
drogen pressure, furnished the cyclopentanone 37, the for three hours in a sealed tube at 125 °C, followed by
structure of which was established from its spectral data. treatment of the hydrazone with potassium hydroxide in
Reaction of the cyclopentanone 37 with ethanedithiol and digol for 12 hours at 190 °C, furnished the deoxygenated
a catalytic amount of iodine12 in dichloromethane at room compound 39, which exhibited TLC and spectral data
temperature for one hour, produced the thioketal 38 in identical to the sample obtained earlier.
79% yield, which, on desulfurisation with Raney nickel in
refluxing ethanol for three hours, quantitatively furnished
Finally, demethylation of the methyl ether 39 with boron
tribromide in anhydrous dichloromethane for one hour,
the deoxygenation product, g-herbertenol methyl ether 39,
furnished g-herbertenol (18) in 89% yield. The structure
the structure of which was established from its NMR
of this target compound was established from 1H and 13C
spectral data.
NMR spectral data, which were found to be identical to
those of the natural product.5
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

68
A. Srikrishna, P. C. Ravikumar
PAPER
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.8 (C), 139.4 (C), 138.7
(C), 122.2 (CH), 115.0 (CH), 111.4 (CH), 54.9 (CH3), 33.2 (CH2),
21.5 (CH3).
MS: m/z (%) = 216 (11) [M + 2]+, 215 (17), 214 (11) [M+], 213 (16),
135 (100), 105 (7), 91 (26).
a
b
COOEt
33
COOEt
83%
96%
OMe
OMe
c
HRMS: m/z [M – Br] calcd for C9H11O: 135.0810; found: 135.0805.
40
41
68%
3-Methoxy-5-methylbenzyl Alcohol (26)
To a stirred solution of the bromide 25 (657 mg, 3.06 mmol) in ace-
tone (15 mL) was added NaHCO3 (321 mg, 3.84 mmol) and H2O
(25 mL). The reaction mixture was refluxed for 5 h then cooled to
r.t. and extracted with EtOAc (3 × 10 mL). The combined organic
layer was washed with brine (15 mL) and dried (Na2SO4). Evapora-
tion of the solvent and purification of the residue on a silica gel col-
umn (EtOAc–hexane, 1:9→3:7) furnished the alcohol 26.
X
COOEt
d
h
99%
89%
OMe
OH
( )-18
OMe
43 X = COOEt
44 X = CH2OH
45 X = CHO
39 X = CH3
e, 85%
f, 86%
42
Yield: 495 mg (80%); oil.
g, 59%
IR (neat): 3379, 1598, 1464, 1325, 1296, 1194, 1152, 1068, 1039,
946, 913, 837 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.70 (1 H, s), 6.66 (1 H, s),
6.58 (1 H, s), 4.56 (2 H, s), 3.77 (3 H, s), 2.31 (3 H, s), 1.73 (1 H, br
s).
Scheme
5
Reagents and conditions: (a) LDA, THF,
CH2=CHCH2Br; (b) PhCH=Ru(PCy3)2Cl2, CH2Cl2; (c) LDA, THF,
HMPA, MeI; (d) H2, 10% Pd/C, EtOH; (e) LAH, Et2O; (f) PCC, silica
gel, CH2Cl2; (g) NH2NH2·H2O, KOH, digol; (h) BBr3, CH2Cl2.
13C NMR (75 MHz, CDCl3 + CCl4): d = 160.0 (C), 142.4 (C), 139.4
(C), 120.1 (CH), 114.2 (CH), 109.3 (CH), 65.3 (CH2), 55.0 (CH3),
21.7 (CH3).
MS: m/z (%) = 152 (100) [M+], 137 (30), 123 (61), 109 (28), 108
(30), 91 (38).
In conclusion, we have accomplished the first total syn-
thesis of ( )-g-herbertenol (18), the first herbertane to be
isolated from a non-herbertus source, thus confirming the
structure of the natural product. In the present synthesis, a
combination of Claisen rearrangement, RCM and alkyla-
tion reactions were employed for the efficient generation
of the requisite cyclopentane containing two vicinal qua-
ternary carbon atoms.
HRMS: m/z [M – OH] calcd for C9H11O: 135.0810; found:
135.0804.
3-Methoxy-5-methylbenzaldehyde (27)
To a stirred suspension of PCC (691 mg, 4.82 mmol) and silica gel
(690 mg) in anhydrous CH2Cl2 (2 mL) was added a solution of the
alcohol 26 (495 mg, 3.21 mmol) in CH2Cl2 (1 mL). The reaction
mixture was stirred at r.t. for 15 min then filtered through a small
silica gel column. The column was eluted with excess CH2Cl2 and
the solvent was evaporated to furnished the benzaldehyde 27.
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 TMS (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 a direct-inlet
mode. Relative intensities are given in parentheses. High-resolution
mass spectra were recorded on a Micromass Q-TOF micro mass
spectrometer using electrospray-ionization mode. Hydrogenation
reactions at atmospheric pressure were carried out using a balloon
filled with hydrogen. Acme 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
standard syringe-septum technique.
Yield: 460 mg (94%); oil.
IR (neat): 3005, 2729, 1700, 1596, 1386, 1333, 1297, 1195, 1158,
1066, 849 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 9.90 (1 H, s), 7.23 (1 H, s),
7.16 (1 H, s), 6.95 (1 H, s), 3.84 (3 H, s), 2.41 (3 H, s).
13C NMR (75 MHz, CDCl3 + CCl4): d = 191.4 (CH), 160.2 (C),
140.0 (C), 138.0 (C), 124.4 (CH), 122.2 (CH), 109.3 (CH), 55.3
(CH3), 21.3 (CH3).
MS: m/z (%) = 150 (100) [M+], 149 (93), 121 (51), 91 (33), 77 (25).
HRMS: m/z [M + Na] calcd for C9H10O2Na: 173.0578; found:
173.0584.
3-Methoxy-5-methylbenzyl Bromide (25)
To a magnetically stirred solution of the anisole 24 (500 mg, 3.68
mmol) in CCl4 (40 mL) was added NBS (622 mg, 3.5 mmol) and
benzoyl peroxide (10 mg). The reaction mixture was refluxed for 1
h then the succinimide was filtered off and the filtrate was succes-
sively washed with 15 mL each of aq HCl (3 N), sat. aq NaHCO3,
H2O and brine. The organic layer was dried (Na2SO4) and the sol-
vent was evaporated to give a residue that was purified on a silica
gel column (CH2Cl2–hexane, 3:7) to furnish the bromide 25.
1-(3-Methoxy-5-methylphenyl)ethanol (28)
To a freshly prepared, magnetically stirred, cold (0 °C) suspension
of MeMgI [prepared from Mg (288 mg, 12.0 mmol) and MeI (0.9
mL, 14.4 mmol) in anhyd Et2O (3 mL)] was added a solution of the
aldehyde 27 (360 mg, 2.4 mmol) in anhyd Et2O (2 mL) over a peri-
od of 10 min. The reaction mixture was stirred at r.t. for 15 min then
poured into ice-cold sat. aq NH4Cl (10 mL) and extracted with Et2O
(3 × 5 mL). The organic extract was washed with brine (7 mL) and
dried (Na2SO4). Evaporation of the solvent furnished the alcohol 28.
Yield: 657 mg (83%); oil.
Yield: 362 mg (91%); oil.
IR (neat): 1597, 1327, 1299, 1214, 1194, 1168, 1154, 1066, 931,
839, 696 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.76 (1 H, s), 6.69 (1 H, s),
6.61 (1 H, s), 4.39 (2 H, s), 3.79 (3 H, s), 2.35 (3 H, s).
IR (neat): 3397, 1598, 1465, 1326, 1293, 1194, 1156, 1153, 1101,
1026, 949, 925 cm–1.
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of ( )-g-Herbertenol
For Z-isomer:
69
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.70 (1 H, s), 6.66 (1 H, s),
6.60 (1 H, s), 4.75 (1 H, q, J = 6.3 Hz), 3.76 (3 H, s, OCH3), 2.31
(3 H, s, ArCH3), 1.95 (1 H, br s, OH), 1.43 (3 H, d, J = 6.3 Hz, sec-
CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.9 (C), 147.5 (C), 139.3
(C), 118.5 (CH), 113.8 (CH), 107.9 (CH), 70.4 (CH), 55.0 (CH3),
25.3 (CH3), 21.6 (CH3).
IR (neat): 1715, 1591, 1461, 1367, 1285, 1221, 1155, 1043, 850,
690 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.61 (1 H, s), 6.55 (1 H, s),
6.50 (1 H, s), 5.82 (1 H, br s), 3.98 (2 H, q, J = 6.9 Hz), 3.75 (3 H,
s), 2.31 (3 H, s), 2.13 (3 H, d, J = 1.2 Hz), 1.09 (3 H, t, J = 6.9 Hz).
13C NMR (75 MHz, CDCl3 + CCl4): d = 165.6 (C), 159.2 (C), 154.8
(C), 142.0 (C), 138.7 (C), 120.0 (CH), 117.8 (CH), 114.0 (CH),
109.8 (CH), 59.6 (CH2), 55.0 (CH3), 27.2 (CH3), 21.7 (CH3), 14.1
(CH3).
MS: m/z (%) = 166 (41) [M+], 151 (28), 123 (100), 108 (25), 91 (22).
HRMS: m/z [M – OH] calcd for C10H13O: 149.0966; found:
149.0966.
MS: m/z (%) = 234 (61) [M+], 220 (7), 205 (10), 189 (57), 188 (100),
175 (16), 160 (28), 145 (19), 115 (21).
3-Methoxy-5-methylacetophenone (22)
Oxidation of the alcohol 28 (300 mg, 1.81 mmol) with PCC (777
mg, 3.6 mmol) and silica gel (780 mg) in dry CH2Cl2 (4 mL) for 1
h at r.t., as described above, followed by purification on a silica gel
column (EtOAc–hexane, 1:10) furnished the ketone 22.
HRMS: m/z [M + Na] calcd for C14H18O3Na: 257.1154; found:
257.1148.
3-(3-Methoxy-5-methylphenyl)but-2-en-1-ol (23)
Yield: 275 mg (93%); oil.
To a cold (–50 °C) magnetically stirred solution of a 12:1 mixture
of the cinnamate 29 (352 mg, 1.5 mmol) in dry Et2O (5 mL) was
added LAH (57 mg, 1.50 mmol) and the mixture was stirred for 1 h.
EtOAc (0.5 mL) was added to consume the excess LAH, then the
reaction was quenched with H2O (10 mL) and extracted with Et2O
(3 × 5 mL). The combined organic extract was washed with brine
(10 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica gel column (EtOAc–hexane, 1:3)
furnished an E/Z mixture of the alcohol 23 (280 mg, 84%).
IR (neat): 3001, 1684, 1594, 1457, 1427, 1358, 1330, 1301, 1218,
1189, 1156, 1064, 973, 930 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 7.30 (1 H, s), 7.23 (1 H, s),
6.87 (1 H, s), 3.80 (3 H, s), 2.50 (3 H, s), 2.40 (3 H, s).
13C NMR (75 MHz, CDCl3 + CCl4): d = 197.0 (C), 159.9 (C), 139.4
(C), 138.5 (C), 122.0 (CH), 120.3 (CH), 109.5 (CH), 55.2 (CH3),
26.6 (CH3), 21.5 (CH3).
MS: m/z (%) = 164 (50) [M+], 149 (100), 121 (47).
E-alcohol:
HRMS: m/z [M + Na] calcd for C10H12O2Na: 187.0735; found:
187.0728.
IR (neat): 3363 (OH), 2920, 2838, 1591, 1453, 1334, 1294, 1205,
1166, 1154, 1064, 997, 847, 696 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.75, 6.67, 6.57 (3 × 1 H,
3 × s, ArH), 5.90 (1 H, td, J = 6.6 Hz, 1.5 Hz, H-2), 4.29 (2 H, d,
J = 6.6 Hz, H-1), 3.77 (3 H, s, OCH3), 2.31 (3 H, s, ArCH3), 2.03
(3 H, s, H-4), 1.70 (1 H, br s, OH).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.6 (C, C-3¢), 144.3 (C),
138.8 (C), 137.8 (C), 126.7 (CH), 119.3 (CH), 113.5 (CH), 108.9
(CH), 59.8 (CH2, C-1), 55.0 (CH3, OCH3), 21.8 (CH3, ArCH3), 16.2
(CH3, C-4).
Ethyl 3-(3-Methoxy-5-methylphenyl)but-2-enoate (29)
A suspension of NaH (256 mg, 60% dispersion in oil, 6.4 mmol) in
hexanes under nitrogen atmosphere was magnetically stirred for 10
min and the solvent was removed by syringe. The oil free NaH was
then suspended in dry THF (3 mL) and cooled in an ice bath. Tri-
ethyl phosphonoacetate (1.33 mL, 6.7 mmol) was added dropwise
and the reaction mixture was stirred at r.t. for 30 min. A solution of
the acetophenone 22 (275 mg, 1.68 mmol) in dry THF (2 mL) was
added drop wise to the reaction mixture and stirred at r.t. for 8 h.
The reaction was then quenched by careful addition of sat. aq
NH4Cl (5 mL) and extracted with Et2O (3 × 4 mL). The combined
organic extract was washed with brine (7 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over a sil-
ica gel column (EtOAc–hexane, 1:20) furnished a 12:1 E/Z mixture
of the cinnamate 29 (352 mg, 90%). Small samples of E- and Z-iso-
mers were separated by careful column chromatography on silica
gel and characterized.
MS: m/z (%) = 192 (100) [M+], 177 (27), 163 (84), 159 (25), 149
(32), 135 (35), 123 (39), 115 (24), 105 (16), 91 (32).
HRMS: m/z [M – OH] calcd for C12H15O: 175.1123; found:
175.1124.
3-(3-Methoxy-5-methylphenyl)-3-methylpent-4-enal (21) and 4-
(3-Methoxy-5-methylphenyl)-3-methylpent-4-enal (30)
A solution of an E/Z mixture of the allyl alcohol 23 (54 mg, 0.28
mmol), ethyl vinyl ether (0.27 mL, 2.8 mmol) and mercuric acetate
(10 mg) was heated at 100 °C in a Carius tube under N2 atmosphere
for 8 h. The excess pressure was then carefully released and the re-
action mixture heated to 175 °C for 16 h. After cooling, the mixture
was diluted with Et2O (5 mL), washed with sat. aq NaHCO3 (3 mL)
brine (3 mL), and dried (Na2SO4). Evaporation of the solvent and
purification of the residue over a silica gel column (EtOAc–hexane,
1:20) furnished a 4:1 mixture of the aldehydes 21 and 30 (42 mg,
64%) as an oil.
E-isomer:
IR (neat): 1715, 1634, 1627, 1591, 1463, 1339, 1222, 1161, 1045,
847, 687 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.83 (1 H, s), 6.74 (1 H, s),
6.66 (1 H, s), 6.06 (1 H, br s), 4.18 (2 H, q, J = 6.9 Hz), 3.79 (3 H,
s), 2.56 (3 H, d, J = 0.9 Hz), 2.34 (3 H, s), 1.30 (3 H, t, J = 6.9 Hz).
13C NMR (75 MHz, CDCl3 + CCl4): d = 166.3 (C), 159.6 (C), 155.5
(C), 143.6 (C), 139.1 (C), 119.5 (CH), 117.1 (CH), 115.1 (CH),
109.1 (CH), 59.5 (CH2), 54.9 (CH3), 21.6 (CH3), 18.0 (CH3), 14.4
(CH3).
IR (neat): 2732, 1718, 1675, 1584, 1372, 1282, 1224, 1179, 1051,
1025, 917, 877, 805, 734, 612 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (signals due to 30) = 9.71
(1 H, t, J = 2.4 Hz, CHO), 6.70, 6.33, 6.61 (3 × 1 H, 3 × s, ArH),
5.19, 5.00 (2 × 1 H, s, H-5), 3.19–3.31 (1 H, m, H-3), 2.70–2.55,
2.45–2.30 (2 × 1 H, 2 × m, H-2), 2.31 (3 H, s, ArCH3), 1.17 (3 H, d,
J = 6.9 Hz, sec-CH3).
MS: m/z (%) = 234 (58) [M+], 189 (60), 188 (100), 160 (28), 145
(20), 131 (12), 115 (20).
HRMS: m/z [M + Na] calcd for C14H18O3Na: 257.1154; found:
257.1165.
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

70
A. Srikrishna, P. C. Ravikumar
PAPER
Ethyl 3-(3-Methoxy-5-methylphenyl)-3-methylpent-4-enoate
(33)
1H NMR (300 MHz, CDCl3 + CCl4): d = 9.52 (1 H, t, J = 3.0 Hz,
CHO), 6.66, 6.61, 6.51 (3 × 1 H, 3 × s, ArH], 6.06 (1 H, dd, J = 17.4
Hz, 10.8 Hz, H-4), 5.18 (1 H, d, J = 10.8 Hz, H-5) and 5.10 (1 H, d,
J 17.1 Hz, H-5), 3.75 (3 H, s, OCH3), 2.75 and 2.66 (2 H, 2 × dd,
J = 15.0 Hz, 3.0 Hz, H-2), 2.32 (3 H, s, ArCH3), 1.49 (3 H, s, tert-
CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 201.3 (CH, CHO), 159.9
(C, C-3¢), 146.8 (C, C-1¢), 145.3 (CH, C-4), 139.2 (C, C-5¢), 119.5
(CH, C-6¢), 113.0 (CH2, C-5), 112.3 (CH), 110.1 (CH), 55.0 (CH3,
OCH3), 53.2 (CH2, C-2), 42.9 (C, C-3), 26.3 (CH3, tert-CH3), 22.0
(CH3, ArCH3).
A solution of the allyl alcohol 23 (240 mg, 1.25 mmol), triethyl
orthoacetate (0.91 mL, 5.0 mmol) and propionic acid (10 ml) was
placed in a sealed tube and heated to 180 °C for 48 h in an oil bath.
The reaction mixture was cooled, diluted with Et2O (5 mL), washed
with HCl (3 M, 5 mL), sat. aq NaHCO3 (5 mL), brine (5 mL) and
then dried (Na2SO4). Evaporation of the solvent and purification of
the residue on a silica gel column (EtOAc–hexane, 1:20) furnished
the pentenoate 33.
Yield: 266 mg (81%); oil.
IR (neat): 1735, 1595, 1463, 1367, 1326, 1294, 1215, 1169, 1155,
1063, 1034, 917, 843, 706 cm–1.
HRMS: m/z [M + Na] calcd for C14H18O2Na: 241.1204; found:
241.1208.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.65, 6.60, 6.49 (3 × 1 H,
3 × s, ArH], 6.11 (1 H, dd, J = 17.4 Hz, 10.8 Hz, H-4), 5.11 (1 H, d,
J = 10.8 Hz, H-5), 5.05 (1 H, d, J = 17.4 Hz, H-5), 3.98 (2 H, q, J =
7.2 Hz, OCH2CH3), 3.75 (3 H, s, OCH3), 2.70, 2.68 (2 H, 2 × d, J =
14.1 Hz, H-2), 2.32 (3 H, s, ArCH3), 1.51 (3 H, s, tert-CH3), 1.14
(3 H, t, J = 7.2 Hz, OCH2CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 170.7 (C, OC=O), 159.6 (C,
C-3¢), 147.6 (C, C-1¢), 145.6 (CH, C-4), 138.6 (C, C-5¢), 119.6 (CH,
C-2), 112.3 (CH2, C-5), 112.1 (CH, C-4), 109.9 (CH), 59.8 (CH2,
OCH2CH3), 54.9 (CH3, OCH3), 45.7 (CH2, C-2), 43.5 (C, C-3), 25.7
(CH3, tert-CH3), 22.0 (CH3, ArCH3), 14.3 (CH3, OCH2CH3).
5-(3-Methoxy-5-methylphenyl)-5-methylhepta-1,6-dien-3-ol
(20)
To a cold (–20 °C) magnetically stirred solution of the aldehyde 21
(145 mg, 0.66 mmol) in THF (3 mL) was added, dropwise, a solu-
tion of vinylmagnesium bromide [prepared from Mg (89 mg, 3.33
mmol) and vinyl bromide (0.28 mL, 3.99 mmol) in THF (5 mL)].
The reaction was stirred at –20 °C for 5 min then quenched with
cold sat. aq NH4Cl (10 mL) and extracted with Et2O (2 × 4 mL). The
organic layer was washed with H2O (5 mL) and brine (5 mL), and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue on a silica gel column (EtOAc–hexane, 1:9), furnished a
~1:1 diastereomeric mixture of the alcohol 20.
MS: m/z (%) = 262 (10) [M+], 175 (100), 174 (67), 159 (22), 149
(9), 128 (7), 115 (9), 105 (10).
Yield: 134 mg (82%); oil.
HRMS: m/z [M + Na] calcd for C16H22O3Na: 285.1467; found:
285.1471.
IR (neat): 3437, 1594, 1456, 1427, 1323, 1291, 1193, 1167, 1154,
1062, 994, 918, 845 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
6.67, 6.62, 6.48 (3 × 1 H, 3 × s, ArH), 6.10 and 6.04 (1 H, dd, J =
17.1 Hz, 10.5 Hz, H-6), 5.85–5.69 (1 H, m, H-2), 5.15–4.90 (4 H,
m, H-1 and H-7), 4.17–4.00 (1 H, m, H-3), 3.74 (3 H, s, OCH3),
2.31 (3 H, s, ArCH3), 2.05–1.82 (2 H, m, H-4), 1.45 and 1.42 (3 H,
s, tert-CH3), 1.30 (1 H, br s, OH).
13C NMR (75 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
159.7 and 159.6 (C, C-3¢), 148.4 and 148.3 (C, C-1¢), 147.4 and
146.8 (CH, C-6), 142.2 and 142.1 (CH, C-2), 138.8 and 138.7 (C,
C-5¢), 119.9 and 119.8 (CH, C-6¢), 113.4 (CH2, C-7), 112.1 and
111.8 (CH2, C-1), 112.0 and 111.9 (CH), 110.3 and 110.2 (CH),
70.3 and 70.2 (CH, C-3), 54.8 (CH3, OCH3), 48.2 (CH2, C-4), 43.9
and 43.8 (C, C-5), 25.8 and 25.6 (CH3, tert-CH3), 22.0 (CH3).
3-(3-Methoxy-5-methylphenyl)-3-methylpent-4-en-1-ol (34)
As described above, reduction of the pentenoate 33 (280 mg, 1.07
mmol) with LAH (40 mg, 1.07 mmol) in dry Et2O (2 mL) at 0 °C
for 30 min, followed by purification on a silica gel column (EtOAc–
hexane, 1:4→3:7), furnished the alcohol 34.
Yield: 228 mg (98%); oil.
IR (neat): 3364, 2943, 1594, 1455, 1327, 1291, 1193, 1166, 1154,
1063, 915, 836, 708 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.65, 6.60, 6.54 (3 × 1 H,
3 × s, ArH), 5.99 (1 H, dd, J = 17.1 Hz, 10.8 Hz, H-4), 5.09 (1 H,
dd, J = 10.8, 1.2 Hz, H-5) and 5.06 (1 H, dd, J = 17.1 Hz, 1.2 Hz, H-
5), 3.75 (3 H, s, OCH3), 3.62–3.42 (2 H, m, CH2OH), 2.30 (3 H, s,
ArCH3), 2.10–1.90 (2 H, m, H-2), 1.37 (3 H, s, tert-CH3), 1.12 (1 H,
br s, OH).
MS: m/z (%) = 176 (100) [M+], 175 (30), 161 (83), 149 (21), 145
(46), 135 (15), 115 (14), 105 (14), 91 (21).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.7 (C, C-3¢), 148.3 (C,
C-1¢), 146.8 (CH, C-4), 138.8 (C, C-5¢), 119.7 (CH, C-6¢), 111.9
(CH2, C-5), 111.9 (CH), 110.1 (CH), 59.9 (CH2, C-1), 54.9 (CH3,
OCH3), 43.5 (CH2), 43.3 (C, C-3), 25.6 (CH3, tert-CH3), 22.0 (CH3,
ArCH3).
MS: m/z (%) = 220 (21) [M+], 174 (70), 175 (100), 161 (45), 160
(27), 145, (30), 115 (12), 105 (18).
HRMS: m/z [M + Na] calcd for C16H22O2Na: 269.1517; found:
269.1519.
4-(3-Methoxy-5-methylphenyl)-4-methylcyclopent-2-en-1-ol
(35)
To a magnetically stirred solution of a 1:1 diastereomeric mixture
of the hydroxydiene 20 (133 mg, 0.54 mmol) in anhydrous CH2Cl2
(20 mL) was added a solution of PhCH=Ru(PCy3)Cl2 (Grubbs cat-
alyst; 22 mg, 5 mol%) in anhydrous CH2Cl2 (34 mL) and the reac-
tion mixture was stirred at r.t. for 1 h. Evaporation of the solvent
under reduced pressure and purification of the residue on a silica gel
column (EtOAc–hexane, 1:10→1:5), furnished a 1:1 diastereomer-
ic mixture of the cyclopentenol 35.
HRMS: m/z [M + Na] calcd for C14H20O2Na: 243.1361; found:
243.1351.
3-(3-Methoxy-5-methylphenyl)-3-methylpent-4-enal (21)
As described above, oxidation of the alcohol 34 (190 mg, 0.86
mmol) with PCC (557 mg, 2.60 mmol) and silica gel (560 mg) in
CH2Cl2 (3 mL), followed by purification on a silica gel column
(EtOAc–hexane, 1:20), furnished the aldehyde 21.
Yield: 105 mg (90%); oil.
IR (neat): 3361, 1606, 1593, 1454, 1324, 1165, 1154, 1061, 1044,
843, 778, 702 cm–1.
Yield: 145 mg (77%); oil.
1H NMR (300 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
6.66 and 6.11 (1 H, s, ArH), 6.58 and 6.53 (1 H, s, ArH) and 6.47
(1 H, s, ArH), 5.98 (1 H, d, J = 5.4 Hz, H-3), 5.83 (1 H, dd, J = 5.4
IR (neat): 2739, 1720, 1595, 1454, 1330, 1296, 1156, 1064, 916,
838, 700 cm–1.
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of ( )-g-Herbertenol
71
Hz, 1.8 Hz, H-2), 4.92–4.80 (1 H, m, H-1), 3.75 and 3.74 (3 H, s,
OCH3), 2.44 (dd, J = 13.5 Hz, 7.5 Hz) and 2.39 (dd, J = 13.5 Hz, 6.9
Hz) [1 H, H-5A], 2.30 and 2.29 (3 H, s, ArCH3), 1.89 (dd, J = 13.5
Hz, 4.8 Hz) and 1.81 (dd, J = 13.5 Hz, 4.2 Hz) [1 H, H-5B], 1.88–
1.78 (1 H, br s, OH), 1.51 and 1.38 (3 H, s, tert-CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 213.0 (C, C=O), 167.7 (CH,
C-3), 159.7 (C, C-3¢), 144.7 (C, C-1¢), 138.9 (C, C-5¢), 129.3 (CH,
C-2), 120.0 (CH, C-6¢), 112.1 (CH), 110.7 (CH), 54.8 (C, C-4), 54.6
(C, C-5), 51.3 (CH3, OCH3), 26.3, 26.0, 20.0 (3 × CH3, tert-CH3],
22.0 (CH3, ArCH3).
13C NMR (75 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
159.7 and 159.6 (C, C-3¢), 150.8 and 150.2 (C, C-1¢), 143.1 and
142.6 (CH, C-3), 138.9 and 138.8 (C, C-5¢), 132.5 and 132.4 (CH,
C-2), 119.0 (CH, C-6¢), 111.8 and 111.6 (CH), 109.3 (CH), 77.2
(CH, C-1), 54.9 (CH3, OCH3), 52.3 and 51.5 (C, C-4), 51.4 and 50.9
(CH2, C-5), 30.1 and 28.6 (CH3, tert-CH3), 21.9 (CH3, ArCH3).
MS: m/z (%) = 244 (37) [M+], 229 (100), 215 (5), 201 (8), 186 (13),
159 (7), 128 (7), 115 (9).
HRMS: m/z [M + Na] calcd for C16H20O2Na: 267.1361; found:
267.1362.
3-(3-Methoxy-5-methylphenyl)-2,2,3-trimethylcyclopentanone
(37)
MS: m/z (%) = 218 (100) [M+], 203 (85), 200 (39), 185 (37), 175
(93), 163 (35), 135 (59), 115 (33).
To activated 10% Pd/C (10 mg) was added a solution of the enone
19 (71 mg, 0.29 mmol) in EtOH (1 mL) and the reaction mixture
was stirred at r.t. for 2 h in an atmosphere of hydrogen created by
evacuative replacement of air (balloon). The catalyst was then fil-
tered off using a small silica gel column. Evaporation of the solvent
furnished the cyclopentanone 37.
HRMS: m/z [M + Na] calcd for C14H18O2Na: 241.1204; found:
241.1197.
4-(3-Methoxy-5-methylphenyl)-4-methylcyclopent-2-enone (36)
To a magnetically stirred suspension of PCC (198 mg, 0.92 mmol)
and anhydrous AcONa (191 mg, 2.3 mmol) in anhydrous CH2Cl2 (3
mL) was added a solution of the allyl alcohol 35 (100 mg, 0.46
mmol) in CH2Cl2 (1 mL). The mixture was stirred at r.t. for 6 h then
filtered through a small silica gel column. The column was eluted
with excess CH2Cl2 and the eluent was evaporated to furnish the cy-
clopentenone 36.
Yield: 71 mg (99%); oil.
IR (neat): 1738, 1607, 1595, 1460, 1376, 1322, 1297, 1155, 1101,
1058, 843, 702 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.75, 6.70, 6.57 (3 × 1 H,
3 × s, ArH), 3.79 (3 H, s, OCH3), 2.70–2.30 (3 H, m), 2.35 (3 H, s,
ArCH3), 1.86 (1 H, ddd, J = 12.3 Hz, 8.4 Hz 1.8 Hz), 1.24, 1.19,
0.63 (3 × 3 H, 3 × s, tert-CH3].
13C NMR (75 MHz, CDCl3 + CCl4): d = 221.4 (C, C=O), 159.5 (C,
C-3¢), 146.5 (C, C-1¢), 138.7 (C, C-5¢), 119.7 (CH, C-6¢), 111.5
(CH), 110.5 (CH), 54.9 (CH3, OCH3), 53.1 (C, C-2), 48.6 (C, C-3),
33.6 (CH2), 29.8 (CH2), 25.5, 22.1, 18.6 (3 × CH3, tert-CH3], 22.0
(CH3, ArCH3).
Yield: 90 mg (91%); oil.
IR (neat): 1716, 1594, 1460, 1328, 1297, 1153, 1053, 835, 799, 701
cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 7.59 (1 H, d, J = 5.4 Hz,
H-3), 6.58 (1 H, s) and 6.50 (2 H, br s) [3 × ArH], 6.16 (1 H, d, J =
5.4 Hz, H-2), 3.76 (3 H, s, OCH3), 2.60 and 2.46 (2 H, 2 × d, J =
18.6 Hz, H-5), 2.31 (3 H, s, ArCH3), 1.60 (3 H, s, tert-CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 208.3 (C, C-1), 170.5 (CH,
C-3), 160.0 (C, C-3¢), 146.8 (C, C-1¢), 139.5 (C, C-5¢), 131.7 (CH,
C-2), 118.9 (CH, C-6¢), 112.4 (CH), 109.4 (CH), 55.0 (CH3, OCH3),
51.8 (CH2, C-5), 48.1 (C, C-4), 27.4 (CH3, tert-CH3), 21.9 (CH3,
ArCH3).
MS: m/z (%) = 246 (56) [M+], 231 (7), 213 (9), 203 (8), 189 (6), 175
(100), 162 (32), 145 (8), 115 (8), 105 (7).
HRMS: m/z [M + Na] calcd for C16H22O2Na: 269.1517; found:
269.1522.
7-(3-Methoxy-5-methylphenyl)-6,6,7-trimethyl-1,4-dithia-
spiro[4.4]nonane (38)
MS: m/z (%) = 216 (81) [M+], 201 (100), 185 (9), 173 (30), 158 (23),
141 (8), 128 (15), 115 (18).
To a magnetically stirred solution of the ketone 37 (63 mg, 0.26
mmol) in dry CH2Cl2 (0.22 mL) was added 1,2-ethanedithiol (0.22
mL, 2.56 mmol) and iodine (7 mg, 10 mol%). The mixture was
stirred at r.t. for 1 h, then aq Na2S2O3 (1 M, 1 mL), followed by aq
NaOH (10%, 5 mL) were added and the reaction was stirred for 5
min. The product was extracted with CH2Cl2 (2 × 3 mL) and the or-
ganic extract was washed with brine (4 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over a sil-
ica gel column (CH2Cl2–hexane, 1:9), furnished the thioketal 38.
HRMS: m/z [M + Na] calcd for C14H16O2Na: 239.1048; found:
239.1045.
4-(3-Methoxy-5-methylphenyl)-4,5,5-trimethylcyclopent-4-
enone (19)
A suspension of NaH (96 mg, 60% dispersion in oil, 2.4 mmol) in
hexanes (1 mL) under nitrogen atmosphere was magnetically stirred
for 10 min and the solvent was removed by syringe. The oil free
NaH was then suspended in dry THF (1 mL) and anhydrous DMF
(0.3 mL), MeI (0.2 mL. 3.18 mmol) and the enone 36 (86 mg, 0.4
mmol) were added sequentially. The reaction mixture was stirred at
r.t. for 12 h then quenched with H2O (3 mL) and extracted with Et2O
(3 × 3 mL). The combined organic extract was washed with brine (5
mL) and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column (EtOAc–hexane, 1:9), fur-
nished the enone 19.
Yield: 65 mg (79%); oil.
IR (neat): 1606, 1593, 1376, 1362, 1320, 1292, 1228, 1191, 1167,
1154, 1094, 1062, 952, 922, 833, 707 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.69, 6.65, 6.48 (3 × 1 H,
3 × s, ArH), 3.76 (3 H, s, OCH3), 3.33–3.10 (4 H, m, SCH2CH2S),
2.70–2.40 (3 H, m), 2.32 (3 H, s, ArCH3), 1.80–1.66 (1 H, m), 1.47,
1.21, 0.70 (3 × 3 H, 3 × s, tert-CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.3 (C, C-3¢), 149.4 (C,
C-1¢), 138.0 (C, C-5¢), 120.3 (CH, C-6¢), 111.0 (2 × C, CH), 82.2 (C,
C-5), 54.9 (CH3, OCH3), 51.8 (C), 50.5 (C), 45.5 (CH2), 40.2 (CH2),
37.9 (CH2), 36.8 (CH2), 28.2, 28.1, 22.2 (3 × CH3, tert-CH3), 21.3
(CH3, ArCH3).
MS: m/z (%) = 322 (10) [M+], 308 (6), 262 (4), 191 (20), 189 (23),
175 (8), 162 (100), 131 (56).
Yield: 72 mg (78%); oil.
IR (neat): 1712, 1594, 1456, 1385, 1324, 1298, 1193, 1170, 1156,
1118, 1061, 707, 623 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 7.65 (1 H, d, J = 5.7 Hz,
H-3), 6.49, 6.48, 6.43 (3 × 1 H, 3 × s, ArH), 6.13 (1 H, d, J = 5.7 Hz,
H-2), 3.72 (3 H, s, OCH3), 2.29 (3 H, s, ArCH3), 1.39, 1.13, 0.52 (3
× 3 H, 3 × s, tert-CH3].
HRMS: m/z [M + Na] calcd for C18H26OS2Na: 345.1323; found:
345.1331.
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

72
A. Srikrishna, P. C. Ravikumar
PAPER
5-Methyl-3-(1,2,2-trimethylcyclopentyl)anisole (g-Herbertenol
Methyl Ether) (39)
Ethyl 2-(3-Methoxy-5-methylphenyl)-2-methylcyclopent-3-ene-
1-carboxylate (41)
To a magnetically stirred solution of the thioketal 38 (65 mg, 0.2
mmol) in dry EtOH (3 mL) was added Raney nickel (100 mg, ex-
cess). The mixture was refluxed for 3 h then cooled and filtered
through a short silica gel column using excess CH2Cl2. Evaporation
of the solvent furnished g-herbertenol methyl ether 39.
To a magnetically stirred solution of a 9:4 diastereomeric mixture
of the diene 40 (203 mg, 0.67 mmol) in anhydrous CH2Cl2 (40 mL)
was added a solution of Grubbs’ I catalyst (25 mg, 5 mol%) in an-
hydrous CH2Cl2 (10 mL). The reaction mixture was stirred at r.t. for
5 h then the solvent was evaporated under reduced pressure and the
residue was purified on a silica gel column (EtOAc–hexane, 1:30),
to furnish a 9:4 diastereomeric mixture of the cyclopentenecarbox-
ylate 41.
Yiled: 47 mg (100%); oil.
IR (neat): 3067, 1607, 1594, 1461, 1427, 1374, 1320, 1295, 1193,
1167, 1154, 1062, 831, 704 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.71, 6.68, 6.49 (3 × 1 H,
3 × s, ArH), 3.76 (3 H, s, OCH3), 2.55–2.35 (1 H, m), 2.32 (3 H, s,
ArCH3), 1.85–1.45 (5 H, m), 1.23, 1.07, 0.57 (3 × 3 H, 3 × s, tert-
CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.1 (C, C-1), 149.1 (C,
C-3), 137.8 (C, C-5), 120.5 (CH, C-6), 111.0 (CH), 110.9 (CH),
54.9 (CH3, OCH3), 50.7 (C, C-1¢), 44.3 (C, C-2¢), 39.9 (CH2), 36.9
(CH2), 26.7, 24.6, 24.4 (3 × CH3, tert-CH3], 22.0 (CH3, ArCH3),
19.6 (CH2, C-4¢).
Yield: 177 mg (96%); oil.
IR (neat): 1733, 1594, 1455, 1370, 1324, 1296, 1192, 1166, 1057,
845, 701 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
6.67 and 6.73 (1 H, s), 6.50 and 6.70 (1 H, s) and 6.49 and 6.53 (1 H,
s) [3 × ArH], 5.86 and 5.78 (1 H, dt, J = 5.8 Hz, 2.4 Hz, H-3), 5.56
and 5.61 (1 H, dt, J = 5.8 Hz, 2.1 Hz, H-4), 3.74–3.55 and 4.30–3.96
(2 H, m, OCH2CH3), 3.71 and 3.76 (3 H, s, OCH3), 3.03 and 3.14
(1 H, t, J = 8.4 Hz, H-1), 3.05–2.85 (1 H, m) and 2.58–2.45 (1 H, m)
[H-5], 2.28 and 2.32 (3 H, s, ArCH3), 1.68 and 1.32 (3 H, s, tert-
CH3), 0.93 (t, J = 6.9 Hz) and 1.26 (t, J = 7.2 Hz) [3 H, OCH2CH3].
13C NMR (75 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
172.5 and 173.2 (C, OC=O), 159.2 and 159.7 (C, C-3¢), 144.2 and
150.0 (C, C-1¢), 138.7 and 138.6 (C, C-5¢), 138.1 and 138.6 (CH, C-
3), 128.4 and 127.9 (CH, C-4), 120.3 and 119.5 (CH, C-6¢), 112.4
and 112.0 (CH), 110.4 and 109.7 (CH), 59.8 and 60.0 (CH2,
OCH2CH3), 55.9 and 55.5 (CH3, OCH3), 55.9 and 55.0 (C, C-2),
54.9 (CH, C-1), 34.6 and 34.5 (CH2, C-5), 27.9 (CH3, tert-CH3),
21.8 (CH3, ArCH3), 13.8 and 14.4 (CH3, OCH2CH3).
MS: m/z (%) = 232 (25) [M+], 175 (2), 163 (34), 162 (32), 150 (100),
135 (20), 115 (8), 105 (6), 91 (14).
HRMS: m/z [M + H]+ calcd for C16H25O: 233.1905; found:
233.1909.
Ethyl 2-Allyl-3-(3-methoxy-5-methylphenyl)-3-methylpent-4-
enoate (40)
To a cold (–70 °C), magnetically stirred solution of diisopropy-
lamine (0.27 mL, 1.93 mmol) in dry THF (4 mL) was added a solu-
tion of n-BuLi (2.2 M in hexane, 0.8 mL, 1.76 mmol). The solution
was stirred for 10 min, then a solution of the ester 33 (230 mg, 0.88
mmol) in dry THF (3 mL) was added dropwise. The reaction mix-
ture was stirred for 40 min then allyl bromide (0.15 mL, 1.76 mmol)
was added and stirring was continued at r.t. for 3 h. The reaction
mixture was then diluted with H2O (5 mL) and extracted with Et2O
(3 × 4 mL). The combined organic extract was washed with aq HCl
(3 M, 5 mL), sat. aq NaHCO3 (5 mL) brine (5 mL) and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
over a silica gel column (EtOAc–hexane, 1:20), furnished a 9:4 dia-
stereomeric mixture of the diene ester 40.
MS: m/z (%) = 274 (76) [M+], 259 (9), 246 (7), 228 (15), 213 (71),
201 (74), 200 (78), 186 (84), 185 (100), 174 (59), 159 (34), 141
(20), 128 (35), 115 (35).
HRMS: m/z [M + Na] calcd for C17H22O3Na: 297.1457; found:
297.1467.
Ethyl 2-(3-Methoxy-5-methylphenyl)-1,2-dimethylcyclopent-3-
en-1-carboxylate (42)
To a cold (–30 °C) magnetically stirred solution of LDA [prepared
from diisopropylamine (0.12 mL, 0.84 mmol) and a solution of n-
BuLi (2.5 M in hexane, 0.29 mL, 0.73 mmol) in anhydrous THF (2
mL)] was added, dropwise, a solution of the ester 41 (100 mg, 0.36
mmol) in a mixture of anhydrous THF (1 mL) and anhydrous
HMPA (1 mL). The reaction was stirred for 40 min at the same tem-
perature then MeI (0.05 mL, 0.73 mmol) was added and stirred at
r.t. for 7 h. The mixture was diluted with H2O (5 mL) and extracted
with Et2O (3 × 4 mL). The combined organic layer was washed with
aq HCl (3 M, 5 mL), sat. aq NaHCO3 (5 mL), brine (7 mL) and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue on a silica gel column (EtOAc–hexane, 1:20), furnished a
4:1 diastereomeric mixture of the ester 42.
Yield: 203 mg (83%); oil.
IR (neat): 1720, 1641, 1595, 1371, 1344, 1323, 1292, 1228, 1184,
1166, 1156, 1063, 995, 918, 845, 702 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
6.72 and 6.70 (1 H, s), 6.66 and 6.67 (1 H, s) and 6.51 (1 H, s)
[3 × ArH], 6.35 and 6.14 (1 H, dd, J = 17.4 Hz, 10.7 Hz, H-4), 5.75–
5.55 (1 H, m, H-2¢), 5.25–4.90 (4 H, m, H-5 and H-3¢), 3.97 and
3.87 (2 H, q, J = 6.9 Hz, OCH2CH3), 3.75 (3 H, s, OCH3), 2.92 (dd,
J = 11.7 Hz, 3.0 Hz) and 2.89 (dd, J = 10.5 Hz, 2.4 Hz) [1 H, H-1¢A],
2.46–2.24 (1 H, m, H-1¢B), 2.31 and 2.30 (3 H, s, ArCH3), 2.05–
1.92 and 2.18–2.11 (1 H, m), 1.47 and 1.46 (3 H, s, tert-CH3), 1.10
and 0.99 (3 H, t, J = 6.9 Hz, OCH2CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
173.3 and 173.2 (C, OC=O), 159.5 (C, C-3¢), 147.2 and 147.1 (C,
C-1¢), 144.0 and 143.4 (CH, C-4), 138.6 (C, C-5¢), 135.9 (CH, C-2¢),
119.9 and 120.0 (CH, C-6¢), 116.4 and 116.3 (CH2, C-3¢), 113.7 and
113.8 (CH2, C-5), 112.0 and 112.1 (CH), 110.2 (CH), 59.7 (CH2,
OCH2CH3), 54.8 and 54.9 (CH, C-1), 54.7 (CH3, OCH3), 46.3 (C,
C-3), 32.8 and 32.7 (CH2, C-1¢), 21.9 (CH3, ArCH3), 20.9 and 21.5
(CH3, tert-CH3), 14.3 and 14.1 (CH3, OCH2CH3).
Yileld: 71 mg (68%); oil.
IR (neat): 3052, 1725, 1594, 1378, 1322, 1291, 1263, 1200, 1167,
1154, 1112, 1055, 1027, 845, 702 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
6.64 and 6.75 (1 H, s), 6.60 and 6.73 (1 H, s), 6.48 and 6.54 (1 H, s)
[3 × ArH], 5.92–5.89 and 5.77–5.73 (1 H, m, H-3), 5.68–5.65 and
5.54–5.51 (1 H, m, H-4), 3.70–3.43 and 4.26–4.13 (2 H, m,
OCH2CH3), 3.73 and 3.77 (3 H, s, OCH3), 3.19 (dt, J = 16.5 Hz, 2.4
Hz) and 3.33 (br d, J = 16.8 Hz) [1 H, H-5A], 2.28 and 2.32 (3 H, s,
ArCH3), 2.11 (ddd, J = 16.5 Hz, 2.4 Hz, 1.2 Hz) and 2.14 (ddd, J =
16.8 Hz, 2.7 Hz, 1.2 Hz) [1 H, H-5B], 1.50 (3 H, s, C2-CH3), 1.34
and 0.79 (3 H, s, C1-CH3), 0.91 and 1.33 (3 H, t, J = 7.2 Hz,
OCH2CH3).
MS: m/z (%) = 302 (3) [M+], 187 (4), 176 (50), 175 (100), 161 (18),
161 (16), 145 (17), 115 (10), 105 (12).
HRMS: m/z [M + Na] calcd for C19H26O3Na: 325.1780; found:
325.1766.
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

PAPER
First Total Synthesis of ( )-g-Herbertenol
73
13C NMR (75 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
175.0 and 175.9 (C, OC=O), 159.2 and 159.1 (C, C-3¢), 145.2 and
145.1 (C, C-1¢), 137.7 and 138.1 (CH, C-3¢), 138.0 (C, C-5¢), 128.6
and 127.3 (CH, C-4), 120.4 and 121.4 (CH), 112.3 and 111.7 (CH),
110.6 and 111.7 (CH), 59.9 and 60.2 (CH2, OCH2CH3), 57.1 and
57.4 (C), 56.9 and 55.8 (C), 54.9 (CH3, OCH3), 43.2 and 42.9 (CH2,
C-5), 22.5 and 24.7 (CH3) and 21.8 and 24.1 (CH3) [2 × tert-CH3],
21.8 and 21.9 (CH3, ArCH3), 14.4 and 13.7 (CH3, OCH2CH3).
(CH2), 35.1 (CH2), 25.3, 22.1 (2 × tert-CH3), 20.3 (CH2, C-4), 19.6
(CH3, ArCH3).
trans-44:
IR (neat): 3398, 1606, 1594, 1463, 1375, 1320, 1295, 1192, 1160,
1155, 1062, 1019, 832, 705 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.70, 6.68, 6.58 (3 × 1 H,
3 × s, ArH], 3.76 (3 H, s, OCH3), 3.70 and 3.64 (2 H, 2 × d, J = 10.5
Hz, CH2OH), 2.60–2.46 (1 H, m), 2.32 (3 H, s, ArCH3), 1.90–1.40
(5 H, m), 1.28 (3 H, s, tert-CH3), 1.30 (1 H, br s, OH), 0.65 (3 H, s,
tert-CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.2 (C, C-3¢), 148.5 (C,
C-1¢), 138.0 (C, C-5¢), 120.8 (CH, C-6¢), 111.5 (CH), 111.2 (CH),
68.9 (CH2, CH2OH), 54.9 (CH3, OCH3), 51.0 (C), 48.9 (C), 38.0
(CH2), 35.2 (CH2), 23.8 (CH3) and 22.2 (CH3) [2 × tert-CH3], 21.6
(CH3, ArCH3), 20.0 (CH2, C-4).
MS: m/z (%) = 288 (10) [M+], 215 (10), 199 (9), 186 (40), 174 (100),
159 (20), 141 (8), 128 (9), 115 (18).
HRMS: m/z [M + Na] calcd for C18H24O3Na: 311.1623; found:
311.1617.
Ethyl 2-(3-Methoxy-5-methylphenyl)-1,2-dimethylcyclo-
pentanecarboxylate (43)
Catalytic hydrogenation of a diastereomeric mixture of the unsatur-
ated ester 42 (71 mg, 0.25 mmol) with activated 10% Pd/C (15 mg)
in EtOH (1.5 mL) for 2 h at 1 atm hydrogen furnished the ester 43.
MS: m/z (%) = 248 (24) [M+], 220 (11), 175 (22), (16), 163 (52), 163
(39), 152 (28), 151 (15) 150 (100), 149 (38), 135 (34), 123 (21), 115
(15), 105 (12).
Yield: 71 mg (99%); oil.
HRMS: m/z [M + Na] calcd for C16H24O2Na: 271.1674; found:
271.1679.
IR (neat): 1718, 1606, 1595, 1381, 1323, 1296, 1192, 1167, 1156,
1142, 1113, 1061, 1026, 833, 704 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
6.66 (1 H, s), 6.63 (1 H, s) and 6.48 and 6.50 (1 H, s) [3 × ArH],
3.85–3.60 (m) and 4.15 (q, J = 7.2 Hz) [2 H, OCH2CH3], 3.74 and
3.75 (3 H, s OCH3), 2.65–2.30 (2 H, m), 2.29 and 2.31 (3 H, s,
ArCH3), 2.10–1.50 (4 H, m), 1.36 and 0.85 (3 H, s, tert-CH3), 1.32
(3 H, s, tert-CH3), 0.90 and 1.31 (3 H, t, J = 7.2 Hz, OCH2CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d (mixture of diastereomers) =
176.2 and 176.5 (C, OC=O), 159.1 (C, C-3¢), 148.0 and 147.4 (C,
C-1¢), 137.8 and 137.7 (C, C-5¢), 119.9 and 120.8 (CH, C-6¢), 111.6
and 111.5 (CH), 110.3 and 111.3 (CH), 59.7 and 60.1 (CH2,
OCH2CH3), 56.4 and 55.4 (C), 54.9 (CH3, OCH3), 51.8 and 52.6
(C), 38.2 and 38.1 (CH2), 36.3 and 36.8 (CH2), 24.7 and 26.5 (CH3)
and, 20.7 and 22.8 (CH3) [2 × tert-CH3], 22.0 and 21.9 (CH3,
ArCH3), 21.3 (CH2, C-4), 13.7 and 14.3 (CH3, OCH2CH3).
2-(3-Methoxy-5-methylphenyl)-1,2-dimethylcyclopentane-1-
carboxaldehyde (45)
Oxidation of a diastereomeric mixture of the alcohol 44 (27 mg,
1.09 mmol) with PCC (117 mg, 0.54 mmol) and silica gel (117 mg)
in CH2Cl2 (1 mL) at r.t. for 30 min, followed by purification on a
silica gel column (EtOAc–hexane, 1:20), furnished a diastereomeric
mixture of the aldehyde 45.
Yield: 23 mg (86%); oil.
IR (neat): 2723, 1717, 1594, 1459, 1320, 1296, 1155, 1059, 833,
705 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d (2:1 diastereomeric mixture) =
9.95 and 9.01 (1 H, s, CHO), 6.69 and 6.66 (1 H, s, ArH) and 6.55–
6.50 (2 H, m, ArH), 3.77 (3 H, s, OCH3), 2.55–2.17 (2 H, m), 2.32
(3 H, s, ArCH3), 2.04–1.44 (4 H, m), 1.27 and 1.39 (3 H, s, tert-
CH3), 0.79 and 1.31 (3 H, s, tert-CH3).
13C NMR (75 MHz, CDCl3 + CCl4): d (2:1 diastereomeric mixture) =
205.4 and 206.1 (CH, CHO), 159.6 (C, C-3¢), 145.8 and 147.5 (C,
C-1¢), 138.9 and 138.7 (C, C-5¢), 119.9 and 120.1 (CH, C-6¢), 112.0
and 111.8 (CH), 110.5 (CH), 58.5 and 58.1 (C, C-1), 54.9 (CH3,
OCH3), 50.4 and 54.1 (C, C-2), 37.8 and 37.5 (CH2), 32.2 and 33.0
(CH2), 24.7 and 25.6 (CH3), 22.0 (CH3, ArCH3), 20.7 and 20.6
(CH2, C-4), 16.8 and 19.0 (CH3).
MS: m/z (%) = 290 (52) [M+], 216 (47), 189 (42), 188 (24), 176
(100), 175 (22), 173 (22), 162 (40), 161 (84), 145 (39), 135 (36),
115 (79), 105 (14).
HRMS: m/z [M + Na] calcd for C18H26O3Na: 313.1780; found:
313.1780.
2-(3-Methoxy-5-methylphenyl)-1,2-dimethylcyclopentyl-
methanol (44)
Reduction of the ester 43 (40 mg, 0.14 mmol) with LAH (26 mg,
0.69 mmol) in Et2O (1 mL) at 0 °C, followed by purification on a
silica gel column using (EtOAc–hexane, 1:9), furnished a diaste-
reomeric mixture of the alcohol 44 (29 mg, 85%) as an oil. Small
samples of cis and trans isomers of 44 were separated by column
chromatography on silica gel (EtOAc–hexane, 1:12) and character-
ized.
MS: m/z (%) = 246 (14) [M+], 218 (48), 203 (8), 176 (40), 175 (100),
163 (22), 162 (35), 161 (35), 160 (18), 150 (31), 149 (22), 135 (23),
115 (18), 105 (18).
HRMS: m/z [M + Na] calcd for C16H22O2Na: 269.1517; found:
269.1503.
cis-44:
5-Methyl-3-(1,2,2-trimethylcyclopentyl)anisole (39)
A solution of the aldehyde 45 (9 mg, 0.037 mmol) and hydrazine
hydrate (0.05 mL, 1.1 mmol) in digol (0.5 mL) was heated to 125 °C
for 3 h in a sealed tube. After cooling to r.t., KOH (61 mg, 1.1
mmol) was added and the reaction mixture and heated to 190 °C for
12 h. The reaction mixture was then cooled to r.t., acidified with aq
HCl (3 M, 5 mL) and extracted with CH2Cl2 (3 × 2 mL). The com-
bined organic extract was washed with brine (3 mL) and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
over a silica gel column (CH2Cl2–hexane, 1:20), furnished g-her-
bertenol methyl ether 39 (5 mg, 59%), which exhibited TLC and
spectral data identical to those of the sample obtained earlier.
IR (neat): 3410, 1606, 1593, 1460, 1377, 1319, 1294, 1194, 1153,
1059, 1028, 949, 922, 833, 706 cm–1.
1H NMR (300 MHz, CDCl3 + CCl4): d = 6.75, 6.71, 6.52 (3 × 1 H,
3 × s, ArH), 3.76 (3 H, s, OCH3), 3.10 and 3.03 (2 H, 2 × d, J = 10.8
Hz, CH2OH), 2.55–2.40 (1 H, m), 2.32 (3 H, s, ArCH3), 1.90–1.50
(5 H, m), 1.28, 1.12 (2 × 3 H, 2 × s, tert-CH3], 0.64 (1 H, br s, OH).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.5 (C, C-3¢), 148.0 (C,
C-1¢), 138.6 (C, C-5¢), 120.0 (CH, C-6¢), 111.5 (CH), 110.8 (CH),
69.4 (CH2, CH2OH), 54.9 (CH3, OCH3), 49.8 (C), 49.4 (C), 37.6
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York

74
A. Srikrishna, P. C. Ravikumar
PAPER
5-Methyl-3-(1,2,2-trimethylcyclopentyl)phenol
(g-Herbertenol) (18)
References
(1) (a) Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y.
Phytochemistry 2000, 55, 247. (b) Asakawa, Y.
Phytochemistry 2001, 56, 297.
(2) Enzell, C.; Erdtman, H. Tetrahedron 1958, 4, 361.
(3) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Chem.
Commun. 1981, 864.
To a cold (–50 °C) magnetically stirred solution of g-herbertenol
methyl ether 39 (6 mg, 0.026 mmol) in dry CH2Cl2 (1 mL), was add-
ed drop wise a solution of BBr3 (1 M in CH2Cl2, 0.1 mL, 0.1 mmol).
The reaction mixture was allowed to come to r.t. and stirred for 1 h
then quenched with sat. aq NaHCO3 (4 mL) and extracted with
CH2Cl2 (3 × 2 mL). The combined organic extract was washed with
brine (4 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue over a silica gel column (EtOAc–hexane,
1: 20), furnished g-herbertenol 18 (5 mg, 89%) as a colorless solid5
that was recrystallized (CH2Cl2–hexane).
(4) (a) Matsuo, A.; Yuki, S.; Nakayama, M.; Hayashi, S. Chem.
Lett. 1982, 463. (b) Matsuo, A.; Nakayama, N.; Nakayama,
M. Phytochemistry 1985, 24, 777. (c) Matsuo, A.; Yuki, S.;
Nakayama, M. J. Chem. Soc., Perkin Trans. 1 1986, 701.
(d) Asakawa, Y.; Matsuda, R.; Schofield, W. B.; Gradstein,
S. R. Phytochemistry 1982, 21, 2471. (e) Matsuo, A.; Yuki,
S.; Nakayama, M. Chem. Lett. 1983, 1041. (f) Buchanan,
M. S.; Connolly, J. D.; Rycroft, D. S. Phytochemistry 1996,
43, 1245.
(5) (a) Feld, H.; Zapp, J.; Becker, H. Phytochemistry 2003, 64,
1335. (b) It is worth noting that the structures of two
sesquiterpenes HM-2 and HM-3, isolated from the
phytopathogenic fungus Helicobasidium mompa,13a were
assigned as herbertenoids. However, recently the structures
were revised as cuparenoids by total synthesis.13b,c
(6) (a) Srikrishna, A.; Satyanarayana, G. Tetrahedron 2006, 47,
1277. (b) Srikrishna, A.; Rao, M. S. Synlett 2002, 340.
(c) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005,
46, 4879; and references cited therein.
Mp: 64–67 °C.
IR (neat): 3337, 1615, 1595, 1458, 1374, 1298, 1227, 1156, 1012,
967, 842, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.71, 6.61, 6.44 (3 × 1 H, 3 × s,
ArH), 4.56 (1 H, s, OH), 2.53–2.40 (1 H, m), 2.30 (3 H, s, ArCH3),
1.85–1.50 (5 H, m), 1.24, 1.08, 0.59 (3 × 3 H, 3 × s, tert-CH3).
13C NMR (75 MHz, CDCl3): d = 154.9 (C, C-1), 149.5 (C, C-3),
138.2 (C, C-5), 120.6 (CH, C-4), 113.2 (CH) and 111.5 (CH) [C-2
and C-6], 50.6 (C, C-1¢), 44.3 (C, C-2¢), 39.9 (CH2), 36.9 (CH2),
26.7, 24.6, 24.5 (3 × CH3, tert-CH3], 21.9 (CH3, ArCH3), 19.8 (CH2,
C-4¢).
MS: m/z (%) = 218 (24) [M+], 204 (6), 175 (5), 161 (20), 149 (34),
148 (49), 136 (100), 121 (26), 108 (8), 91 (15).
(7) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013.
(c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
(8) Attempts at converting the bromide 25 into the aldehyde 27
using the Kornblum oxidation gave a mixture of the
aldehyde 27 and the alcohol 26.
Acknowledgment
We thank Prof. Becker and Dr. Feld for providing the copies of the
NMR spectra of natural g-herbertenol. P.C.R. thanks the CSIR,
New Delhi for the award of a research fellowship.
(9) Thomas, A. F. J. Chem. Soc., Chem. Commun. 1967, 947.
(10) Srikrishna, A.; Krishnan, K.; Venkateswarlu, S. J. Chem.
Soc., Chem. Commun. 1993, 143.
(11) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T. T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741.
(12) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem.
2001, 66, 7527.
(13) (a) Kajimoto, T.; Yamashita, M.; Imamura, Y.; Takahashi,
K.; Nohara, T.; Shibata, M. Chem. Lett. 1989, 527.
(b) Srikrishna, A.; Ravikumar, P. C. Tetrahedron Lett. 2005,
46, 6105. (c) Srikrishna, A.; Ravikumar, P. C. Tetrahedron
2006, 62, 9393.
Synthesis 2007, No. 1, 65–74 © Thieme Stuttgart · New York