The first total synthesis of (±)-herbertenones A and B

Article abstract of DOI:10.1055/s-2008-1072560

The first total synthesis of (±)-herbertenones A and B, employing Claisen rearrangement-metathesis reaction based approaches, is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072560

PAPER
1527
The First Total Synthesis of ( )-Herbertenones A and B
Total
S
ynthesis of
d
(
)-Herberte
u
nones Aand
s
B
umilli Srikrishna,* Ponneri C. Ravikumar, Hema S. Krishnan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax +91(80)23600529; E-mail: ask@orgchem.iisc.ernet.in
Received 7 December 2007
14
15
Abstract: The first total synthesis of ( )-herbertenones A and B,
employing Claisen rearrangement–metathesis reaction based ap-
proaches, is described.
1
5
7
3
9
13
Key words: total synthesis, natural products, rearrangement, ring-
closure, metathesis
1 (cuparene)
2 (herbertene)
X
O
Y
R
X
OH
OH
OH
Liverworts from the genus Herbertus contain herbertane
sesquiterpenoids, which are considered as chemical mark-
ers of the genus.1 The herbertanes are a small group of ar-
omatic sesquiterpenes, isomeric to cuparanes, containing
a sterically crowded 1-aryl-1,2,2-trimethylcyclopentane
carbon framework incorporating two vicinal quaternary
carbon atoms on a cyclopentane ring. Even though cu-
parene (1), isomeric to herbertene (2), has been known2
since 1958, the herbertane family of sesquiterpenes was
reported only in the 1980s. The first member of the fami-
ly, herbertene (2) was isolated in 1981 by Matsuo and co-
workers from the ethyl acetate extract of the liverwort
Herberta adunca (Dicks) S. Gray belonging to the family
herbertaceae.3 Subsequently a few other phenolic herber-
tanes 3–9 were isolated from a variety of Herbertus sourc-
es (Figure 1).4 In 2000, Asakawa and co-workers
reported5 the isolation of seven herbertenes, herbertene-
acetal (10), herbertene-1,14-diol (11), herbertene-1,15-
diol (12), herbertenones A and B (13 and 14), herbertene-
1,13-diol (15), and 12-methoxyherbertenediol (16) from
the diethyl ether and ethyl acetate extracts of the Japanese
liverwort Herbertus sakuraii. The herbertane sesquiter-
penes, mainly the phenolic herbertanes, have been shown
to possess interesting biological properties such as growth
inhibiting activity and antilipid peroxidation activity.1,4
Z
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
O
HO
OH
OH
Me
OH
13 β-Me
14 α-Me
OH
MeOH2C
15
16
Figure 1
ring is disturbed, perhaps produced by biogenetic oxida-
tion of a-herbertenol (3). So far, there are no reports in the
literature on the synthesis of herbertenones A and B. In
continuation of our interest in the synthesis of sesquiter-
penes containing contiguous quaternary carbon atoms,7
herein, we describe the first total synthesis of ( )-her-
bertenones A and B (13 and 14), employing a combination
of Claisen rearrangement and ring-closing metathesis
(RCM) reaction based methodologies.6c
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-
cal properties associated with the phenolic herbertanes
make herbertenoids interesting and challenging synthetic
targets. Prior to 1999, there were only three reports ap-
peared in the literature on the synthesis of phenolic her-
bertanes. However, during the last eight years, more than
forty reports have appeared in the literature on the synthe-
sis of phenolic herbertanes making it a topic of contempo-
rary interest.6 Herbertenones A and B (13 and 14) are the
only members of the group where the aromaticity of the A
Retrosynthetic analysis is depicted in Scheme 1. It was
contemplated that 1,4-dimethoxybenzene could be em-
ployed as a masked benzoquinone, which can be convert-
ed into the 4-hydroxy-4-methylcyclohexa-2,5-dienone
moiety present in herbertenones 13 and 14 at the end of
the sequence. It was anticipated6c that 4-aryl-4,5,5-tri-
methylcyclopentenone 17, containing the requisite two
vicinal quaternary carbons, could be obtained from the
hydroxydiene 18 via an RCM reaction.8 The hydroxy-
diene 18 could be prepared from the dimethoxyacetophe-
none 19 via the allyl alcohol 20 and the aldehyde 21.
First attention was focused on the synthesis of the cyclo-
pentenone 17 starting from the acetophenone 19
(Scheme 2). Horner–Wadsworth–Emmons reaction of
acetophenone 19 with triethyl phosphonoacetate and sodi-
um hydride in refluxing tetrahydrofuran furnished a 5:2
SYNTHESIS 2008, No. 10, pp 1527–1534
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072560; Art ID: P14407SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

1528
A. Srikrishna et al.
PAPER
HO
O
MeO
MeO
OH
O
OMe
OMe
18
13,14
17
O
O
OH
MeO
MeO
MeO
H
OMe
OMe
21
OMe
20
19
Scheme 1
X
E/Z mixture of the cinnamate 22, which on regioselective
reduction with lithium aluminum hydride at low tempera-
ture gave an E/Z mixture of the allyl alcohol 20. Johnson’s
ortho ester variant9 of the Claisen rearrangement was cho-
sen for the generation of the first quaternary carbon atom.
Thus, thermal activation of the allyl alcohol 20 with trieth-
yl orthoacetate in the presence of a catalytic amount of
propanoic acid in a sealed tube at 180 °C for 36 hours gen-
erated the g,d-unsaturated ester 23 in 78% yield, whose
structure was established from its spectral data. Reduction
of the ester 23 with lithium aluminum hydride furnished
the primary alcohol 24, which on oxidation with pyridini-
um chlorochromate and silica gel furnished the aldehyde
21. Grignard reaction of the aldehyde 21 with vinylmag-
nesium bromide at room temperature generated, as ex-
pected, a 1:1 epimeric mixture of the hydroxydiene 18 in
86% yield. Treatment of the hydroxydiene 18 with
OMe
MeO
OMe
OMe
O
a
c
X
78%
92%
OMe
OMe
23 X = COOEt
24 X = CH2OH
21 X = CHO
d, 95%
e, 70%
22 X = COOEt
20 X = CH2OH
19
b, 92%
f
86%
g
MeO
MeO
93%
OH
OH
OMe
OMe
25
h
93%
18
MeO
MeO
i
5
mol% of Grubbs’ first-generation catalyst
O
72%
[PhCH=Ru(PCy3)2Cl2] in anhydrous dichloromethane at
room temperature for one hour furnished a 1:1 diastereo-
meric mixture of the cyclopentenol 25 in 93% yield,
which on oxidation with pyridinium chlorochromate and
anhydrous sodium acetate furnished the cyclopentenone
26 in 93% yield, whose structure was established from its
spectral data. Reaction of the cyclopentenone 26 with so-
dium hydride and methyl iodide in anhydrous tetrahydro-
furan and N,N-dimethylformamide at room temperature
generated the enone 17 in 72% yield. Hydrogenation of
the enone 17 using 10% palladium over carbon as the cat-
alyst with one bar pressure (balloon) of hydrogen in etha-
nol furnished the cyclopentanone 27. Reaction of the
cyclopentanone 27 with ethane-1,2-dithiol and a catalytic
amount of iodine10 in dichloromethane at room tempera-
ture produced the thioketal 28 in 81% yield. Desulfuriza-
tion of the thioketal 28 with Raney nickel in refluxing
ethanol furnished quantitatively the deoxygenation prod-
uct, norherbertane 29, whose structure was established
from its spectral data.
O
OMe
OMe
26
j 96%
17
MeO
MeO
MeO
S
l
k
O
S
100%
81%
OMe
OMe
OMe
29
28
27
Scheme 2 Reaction conditions: (a) (EtO)2P(O)CH2CO2Et, NaH,
THF; (b) LAH, Et2O; (c) MeC(OEt)3, EtCO2H, heat; (d) LAH, Et2O;
(e) PCC, silica gel, CH2Cl2; (f) H2C=CHMgBr, THF; (g)
PhCH=Ru(PCy3)2Cl2, CH2Cl2; (h) PCC, NaOAc, CH2Cl2; (i) NaH,
THF, DMF, MeI; (j) H2, 10% Pd/C, EtOH; (k) I2, (CH2SH)2, CH2Cl2;
(k) Raney Ni, EtOH.
meric mixture of the ester 30 in 84% yield. RCM reaction
of the diene ester 30 with 5 mol% of Grubbs’ first-gener-
ation catalyst in anhydrous dichloromethane at room tem-
perature furnished the ester 31 in near quantitative yield.
Generation of the lithium enolate of the ester 31 with lith-
ium diisopropylamide in tetrahydrofuran and hexameth-
ylphosphoramide at –30 °C followed by treatment with
methyl iodide furnished the alkylated product 32 in 88%
An alternative strategy6c was also investigated for the syn-
thesis of 29 starting from the g,d-unsaturated ester 23
(Scheme 3) via the RCM reaction of the ester 30. Genera-
tion of the lithium enolate of the ester 23 with lithium di-
isopropylamide in tetrahydrofuran at –70 °C followed by
alkylation with allyl bromide generated a 1:1 diastereo-
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Herbertenones A and B
1529
yield, in a highly stereoselective manner, via the approach
of the electrophile from the less hindered face of the eno-
late (opposite to aryl group). Catalytic hydrogenation us-
ing 10% palladium over carbon transformed the ester 32
in to the saturated ester 33 in 99% yield. The ester in 32
was converted into a methyl group in three steps. Thus, re-
duction of the ester 33 with lithium aluminum hydride in
diethyl ether at 0 °C furnished the primary alcohol 34,
which on oxidation with pyridinium chlorochromate and
silica gel generated the aldehyde 35. Treatment of the al-
dehyde 35 with hydrazine hydrate in diethylene glycol in
a sealed tube at 125 °C followed by treatment of the hy-
drazone with potassium hydroxide in diethylene glycol at
200 °C furnished the deoxygenated compound 29, which
exhibited TLC and spectral data identical to the sample
obtained earlier.
O
MeO
a
O
53%
OMe
29
O
b
98%
O
O
37
HO
OH
38
OH
a
100%
13
(2:1)
+
O
c
67%
O
MeO
O
MeO
HO
36
14
a
b
23
Scheme 4 Reaction conditions: (a) CAN, MeCN; (b) BBr3, CH2Cl2;
COOEt
84%
97%
COOEt
30
(c) MeMgBr, Et2O.
OMe
c
OMe
31
88%
In conclusion, we have accomplished the first total syn-
thesis of ( )-herbertenones A and B (13 and 14), confirm-
ing the structures of the natural products. In the present
synthesis, a combination of Claisen rearrangement, RCM,
and alkylation reactions were employed for the efficient
generation of the requisite cyclopentane containing two
vicinal quaternary carbon atoms.
MeO
OMe
d
99%
COOEt
X
OMe
OMe
33 X = COOEt
32
e, 93%
34 X = CH2OH
35 X = CHO
29 X = Me
f, 92%
g, 82%
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, and samples were prepared using a 1:1
mixture of CDCl3 and CCl4 as solvent and either internal TMS (for
1H) or the central line (d = 77.0) of CDCl3 (for 13C) as reference. In
13C NMR spectra, the nature of the carbons (C, CH, CH2, or CH3)
was determined by recording DEPT-135 spectra and is given in pa-
rentheses. LRMS spectra were recorded using a Shimadzu QP-
5050A GCMS instrument using direct inlet mode. HRMS were re-
corded on a Micromass Q-TOF micro mass spectrometer using ESI
mode. Hydrogenation reactions at 1 bar pressure were carried out
using a balloon filled with H2. Acme’s silica gel (100–200 mesh)
was used for column chromatography (approximately 15–20 g per
1 g of the crude product). All small-scale dry reactions were carried
out using standard syringe-septum techniques.
Scheme 3 Reaction conditions: (a) LDA, THF, H2C=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, diethylene glycol, KOH.
Next conversion of the aromatic moiety in 29 into a qui-
none via direct oxidation of the norherbertane 29 into the
benzoquinone 36 using ceric ammonium nitrate11 was in-
vestigated (Scheme 4). However, treatment of the norher-
bertanediol dimethyl ether 29 with ceric ammonium
nitrate in aqueous acetonitrile (1:1) furnished the bis-
quinone 37. Hence, a two-step methodology was carried
out for the conversion of dimethyl ether 29 into benzo-
quinone 36. Accordingly, treatment of the dimethyl ether
29 with boron tribromide in anhydrous dichloromethane
furnished the diol 38 in 98% yield. Oxidation of the diol
38 with ceric ammonium nitrate in aqueous acetonitrile
furnished the benzoquinone 36 in quantitative yield,
Ethyl 3-(2,5-Dimethoxyphenyl)but-2-enoate (22)
A suspension of NaH (278 mg, 60% dispersion in oil, 6.94 mmol)
in hexanes under a N2 atmosphere was magnetically stirred for 10
min and the solvent was syringed out. The oil-free NaH was then
suspended in anhyd THF (4 mL) and cooled in an ice bath. Triethyl
whose structure was established from its spectral data. phosphonoacetate (1.65 mL, 8.34 mmol) was added dropwise and
the mixture was stirred at r.t. for 30 min. A soln of 19 (500 mg, 2.78
Finally, Grignard reaction of the benzoquinone 36 with
mmol) in anhyd THF (2 mL) was added dropwise to the mixture and
one equivalent of methylmagnesium bromide in anhy-
it was stirred at r.t. for 4 h. The reaction was then quenched by care-
ful addition of sat. aq NH4Cl soln and extracted with Et2O (3 × 4
mL). The combined Et2O extracts were washed with brine and dried
(Na2SO4). Evaporation of the solvent followed by column chroma-
tography (silica gel, EtOAc–hexane, 1:20) furnished a 5:2 E/Z-
drous tetrahydrofuran at –30 °C for two minutes furnished
a 2:1 mixture of herbertenones A and B (13 and 14),
1
which exhibited H and 13C NMR and GC-MS spectral
data identical5 to those reported for the natural products.
mixture of 22 (638 mg, 92%). Small samples of E and Z-isomers
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York

1530
A. Srikrishna et al.
PAPER
were separated by careful column chromatography (silica gel) and
characterized.
NaHCO3 (5 mL), and brine, and dried (Na2SO4). Evaporation of the
solvent and column chromatography (silica gel, EtOAc–hexane,
1:40) furnished 23 (415 mg, 78%) as an oil.
E-Isomer
IR (neat): 1732, 1635, 1608, 1585, 1497, 1465, 1418, 1367, 1302,
1282, 1224, 1180, 1118, 1031, 916, 873, 803, 734, 703 cm–1.
IR (neat): 1713, 1633, 1584, 1497, 1465, 1420, 1367, 1337, 1310,
1288, 1264, 1215, 1181, 1160, 1095, 1069, 1044, 945, 871, 806,
751, 705, 608 cm–1.
1H NMR: d = 6.75 (br s, 2 H), 6.66 (br s, 1 H), 5.84 (s, 1 H), 4.16
(q, J = 6.9 Hz, 2 H), 3.75 (s, 3 H), 3.73 (s, 3 H), 2.44 (s, 3 H), 1.29
(t, J = 6.9 Hz, 3 H).
13C NMR: d = 166.4 (C), 156.3 (C), 153.5 (C), 150.5 (C), 134.0 (C),
119.4 (CH), 114.8 (CH), 113.8 (CH), 112.2 (CH), 59.6 (CH2), 56.0
(CH3), 55.6 (CH3), 19.8 (CH3), 14.5 (CH3).
1H NMR: d = 6.78 (d, J = 3.0 Hz, 1 H), 6.71 (d, J = 8.7 Hz, 1 H),
6.63 (dd, J = 8.7, 3.0 Hz, 1 H), 6.28 (dd, J = 17.1, 10.5 Hz, 1 H),
5.00 (d, J = 10.5 Hz, 1 H), 4.95 (d, J = 17.1 Hz, 1 H), 3.91 (q,
J = 7.2 Hz, 2 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 3.04 and 2.83 (2 d,
J = 14.4 Hz, 2 H), 1.53 (s, 3 H), 1.04 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 171.3 (C), 153.4 (C), 152.2 (C), 145.6 (CH), 135.2
(C), 115.3 (CH), 112.3 (CH), 111.5 (CH2), 111.0 (CH), 59.5 (CH2),
55.5 (CH3), 55.3 (CH3), 43.5 (CH2), 42.9 (C), 24.6 (CH3), 14.2
(CH3).
MS: m/z (%) = 250 (M+, 26), 219 (55), 205 (16), 191 (100), 161
(20), 162 (18), 147 (20).
MS: m/z (%) = 278 (M+, 38), 191 (100).
HRMS: m/z [M + Na] calcd for C16H22NaO4: 301.1416; found:
301.1405.
Z-Isomer
IR (neat): 1725, 1649, 1583, 1498, 1465, 1370, 1277, 1223, 1180,
1155, 1139, 1046, 805 cm–1.
3-(2,5-Dimethoxyphenyl)-3-methylpent-4-en-1-ol (24)
Reduction of 23 (410 mg, 1.5 mmol) with LAH (56 mg, 1.5 mmol)
in anhyd Et2O (2 mL) at 0 °C for 30 min, followed by column chro-
matography (silica gel, EtOAc–hexane, 1:3) furnished 34 (334 mg,
95%) as an oil.
1H NMR: d = 6.80–6.65 (m, 2 H), 6.54 (d, J = 3 Hz, 1 H), 5.88 (br
s, 1 H), 3.95 (q, J = 7.2 Hz, 2 H), 3.72 (s, 6 H), 2.12 (s, 3 H), 1.06
(t, J = 7.2 Hz, 3 H).
13C NMR: d = 165.2 (C), 153.4 (C), 152.5 (C), 149.6 (C), 131.4 (C),
119.1 (CH), 114.2 (CH), 112.8 (CH), 111.8 (CH), 59.4 (CH2), 56.1
(CH3), 55.5 (CH3), 26.2 (CH3), 14.1 (CH3).
MS: m/z (%) = 250 (M+, 30), 236 (10), 219 (54), 205 (19), 191
(100), 177 (9), 165 (19), 161 (23), 147 (23), 135 (10), 119 (8), 103
(11), 91 (20).
IR (neat): 3380, 1633, 1608, 1584, 1495, 1417, 1282, 1223, 1180,
1051, 912, 875, 803, 733 cm–1.
1H NMR: d = 6.75 (d, J = 3.0 Hz, 1 H), 6.72 (d, J = 8.7 Hz, 1 H),
6.62 (dd, J = 8.7, 3.0 Hz, 1 H), 6.18 (dd, J = 17.7, 10.8 Hz, 1 H),
4.98 (dd, J = 10.8, 1.2 Hz, 1 H), 4.94 (dd, J = 17.7, 1.2 Hz, 1 H),
3.73 (s, 3 H), 3.71 (s, 3 H), 3.52–3.30 (m, 2 H), 2.32 and 2.03
(2 ddd, J = 13.5, 8.1, 6.0 Hz, 2 H), 1.42 (s, 3 H), 1.50–1.40 (br s, 1
H).
HRMS: m/z [M + Na] calcd for C14H18NaO4: 273.1103; found:
273.1105.
3-(2,5-Dimethoxyphenyl)but-2-en-1-ol (20)
13C NMR: d = 153.4 (C), 152.3 (C), 146.7 (CH), 135.9 (C), 115.4
(CH), 112.5 (CH), 111.0 (CH2), 110.6 (CH), 60.1 (CH2), 55.7
(CH3), 55.3 (CH3), 43.0 (C), 41.4 (CH2), 24.9 (CH3).
MS: m/z (%) = 236 (M+, 44), 191 (100), 176 (11), 161 (19), 160
(17), 149 (9), 137 (8), 121 (15).
To a cold (–50 °C) magnetically stirred soln of a 5:2 mixture of 22
(960 mg, 3.84 mmol) in anhyd Et2O (5 mL) was added LAH (146
mg, 3.84 mmol) and stirred for 1 h. EtOAc (0.5 mL) was added to
the mixture to consume the excess LAH. The reaction was then
quenched with H2O (10 mL) and extracted with Et2O (3 × 5 mL).
The combined Et2O extracts were washed with brine and dried
(Na2SO4). Evaporation of the solvent and column chromatography
of the residue (silica gel, EtOAc–hexane, 1:3) furnished an E/Z mix-
ture of 20 (735 mg, 92%).
HRMS: m/z [M + Na] calcd for C14H20NaO3: 259.1310; found:
259.1316.
3-(2,5-Dimethoxyphenyl)-3-methylpent-4-enal (21)
To a magnetically stirred suspension of PCC (752 mg, 3.5 mmol)
and NaOAc (697 mg, 8.40 mmol) in anhyd CH2Cl2 (2 mL) was add-
ed a soln of 24 (330 mg, 1.4 mmol) in CH2Cl2 (3 mL) and the mix-
ture was stirred at r.t. for 2 h. It was then filtered through a small
column (silica gel, excess CH2Cl2). Evaporation of the solvent fur-
nished 21 (225 mg, 70%) as an oil.
E-Isomer
IR (neat): 3397, 1582, 1496, 1419, 1283, 1261, 1220, 1178, 1147,
1099, 1047, 1023, 873, 804, 747, 709 cm–1.
1H NMR: d = 6.74–6.60 (m, 3 H), 5.63 (t, J = 6.6 Hz, 1 H), 4.26 (d,
J = 6.6 Hz, 2 H), 3.73 (s, 3 H), 3.72 (s, 3 H), 2.19 (br s, 1 H), 1.97
(s, 3 H).
13C NMR: d = 153.5 (C), 150.7 (C), 137.8 (C), 134.8 (C), 128.6
(CH), 115.4 (CH), 112.5 (CH), 111.8 (CH), 59.3 (CH2), 55.9 (CH3),
55.5 (CH3), 17.2 (CH3).
MS: m/z (%) = 208 (M+, 100), 193 (27), 177 (23), 175 (25), 165
(91), 150 (33), 137 (26), 135 (26), 121 (20), 115 (20), 105 (31), 91
(39).
IR (neat): 2735, 1719, 1607, 1584, 1495, 1416, 1282, 1225, 1180,
1053, 1025, 918, 878, 805, 732 cm–1.
1H NMR: d = 9.46 (s, 1 H), 6.82 (d, J = 3.0 Hz, 1 H), 6.78 (d, J = 9.3
Hz, 1 H), 6.69 (dd, J = 9.3, 3.0 Hz, 1 H), 6.22 (dd, J = 17.4, 10.8 Hz,
1 H), 5.10 (d, J = 10.8 Hz, 1 H), 5.01 (d, J = 17.4 Hz, 1 H), 3.77 (s,
3 H), 3.73 (s, 3 H), 3.04 and 2.85 (2 d, J = 15.6 Hz, 2 H), 1.53 (s, 3
H).
13C NMR: d = 202.4 (CH), 153.5 (C), 151.8 (C), 145.1 (CH), 134.2
(C), 115.4 (CH), 112.5 (CH), 112.2 (CH2), 111.3 (CH), 55.5 (CH3),
55.4 (CH3), 51.5 (CH2), 42.2 (C), 25.4 (CH3).
HRMS: m/z [M – OH] calcd for C12H15O2: 191.1072; found:
191.1076.
MS: m/z (%) = 234 (49, M+), 191 (100), 176 (7), 161 (16), 160 (17),
121 (14).
Ethyl 3-(2,5-Dimethoxyphenyl)-3-methylpent-4-enoate (23)
A soln of 20 (397 mg, 1.91 mmol), triethyl orthoacetate (1.4 mL,
7.65 mmol), and EtCO2H (10 mL) was placed in a sealed tube and
heated to 180 °C for 36 h in an oil bath. The mixture was cooled,
diluted with Et2O (5 mL), washed with 3 M HCl (5 mL), sat. aq
HRMS: m/z [M + Na] calcd for C14H18NaO3: 257.1154; found:
257.1152.
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Herbertenones A and B
1531
5-(2,5-Dimethoxyphenyl)-5-methylhepta-1,6-dien-3-ol (18)
To a cold (–20 °C) magnetically stirred soln of 21 (225 mg, 0.96
mmol) in THF (4 mL) was added dropwise a soln of vinylmagne-
sium bromide [prepared from Mg (234 mg, 9.60 mmol) and vinyl
bromide (0.8 mL, 11.52 mmol) in THF (8 mL)] and stirred at –20
°C for 5 min. The reaction was quenched with cold sat. aq NH4Cl
(10 mL) and extracted with Et2O (2 × 4 mL). The organic layer was
washed with H2O and brine and dried (Na2SO4). Evaporation of the
solvent and column chromatography of the residue (silica gel,
EtOAc–hexane, 1:9) furnished a ~1:1 diastereomeric mixture of 18
(217 mg, 86%) as an oil.
1H NMR: d = 7.75 (d, J = 5.7 Hz, 1 H), 6.80–6.60 (m, 3 H), 6.13 (d,
J = 5.7 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 2.72 and 2.53 (2 d,
J = 18.6 Hz, 2 H), 1.56 (s, 3 H).
13C NMR: d = 209.0 (C), 169.8 (CH), 153.4 (C), 151.7 (C), 134.5
(C), 131.4 (CH), 114.4 (CH), 112.1 (CH), 111.0 (CH), 55.5 (CH3),
55.4 (CH3), 50.0 (CH2), 47.1 (C), 27.4 (CH3).
MS: m/z (%) = 233 (M + H, 17), 232 (M+, 100), 217 (59), 202 (7),
189 (21), 174 (16), 163 (15), 115 (15).
HRMS: m/z [M + H] calcd for C14H17O3: 233.1177; found:
233.1177.
IR (neat): 3452, 1634, 1607, 1585, 1492, 1464, 1281, 1223, 1180,
1051, 1027, 991, 918, 876, 802, 734 cm–1.
4-(2,5-Dimethoxyphenyl)-4,5,5-trimethylcyclopent-2-enone
(17)
1H NMR: d (mixture of diastereomers) = 6.83 and 6.82 (d, J = 3.0
Hz, 1 H), 6.75 and 6.74 (d, J = 8.7 Hz, 1 H), 6.67 (dd, J = 8.7, 3 Hz)
and 6.65 (dd, J = 8.7, 2.7 Hz) [1 H], 6.31 and 6.29 (dd, J = 17.4,
10.8 Hz, 1 H), 5.85–5.65 (m, 1 H), 5.10–4.86 (m, 4 H), 4.10–3.90
(m, 1 H), 3.75 and 3.74 (s, 3 H), 3.73 (s, 3 H), 2.35–2.20 (m, 1 H),
2.05–1.95 (m, 1 H), 1.53 and 1.46 (s, 3 H), 1.50 (br s, 1 H).
13C NMR: d (mixture of diastereomers) = 153.5 (C), 152.3 (C),
147.2 and 147.1 (CH), 142.3 and 142.2 (CH), 135.9 (C), 115.6
(CH), 113.1 and 113.0 (CH2), 112.5 and 112.4 (CH), 111.0 (CH2),
110.9 and 110.7 (CH), 70.9 and 70.8 (CH), 55.6 (CH3), 55.3 (CH3),
46.2 and 45.8 (CH2), 43.6 (C), 25.4 and 25.3 (CH3).
A suspension of NaH (150 mg, 60% dispersion in oil, 3.75 mmol)
in hexanes (1 mL) under a N2 atmosphere was magnetically stirred
for 10 min and the solvent was syringed out. The oil free NaH was
then suspended in anhyd THF (3 mL), added sequentially, anhyd
DMF (0.4 mL), MeI (0.31 mL, 5.04 mmol), and 26 (145 mg, 0.63
mmol). The mixture was magnetically stirred at r.t. for 12 h. It was
then quenched with H2O (3 mL) and extracted with Et2O (3 × 4
mL). The combined Et2O extracts were washed with brine and dried
(Na2SO4). Evaporation of the solvent and column chromatography
(silica gel, EtOAc–hexane, 1:9) furnished 17 (117 mg, 72%) as an
oil.
MS: m/z (%) = 262 (M+, 84), 192 (100), 176 (33), 175 (30), 161
(75), 160 (65), 149 (29), 139 (70), 121 (53), 115 (33).
IR (neat): 1708, 1585, 1500, 1381, 1339, 1285, 1228, 1180, 1120,
1081, 1041, 1025, 839, 804, 765, 729 cm–1.
HRMS: m/z [M + Na] calcd for C16H22NaO3: 285.1467; found:
285.1478.
1H NMR: d = 7.83 (d, J = 5.7 Hz, 1 H), 6.78 (d, J = 9.3 Hz, 1 H),
6.69 (dd, J = 9.3, 3.0 Hz, 1 H), 6.60 (br s, 1 H), 6.09 (d, J = 5.7 Hz,
1 H), 3.79 (s, 3 H), 3.74 (s, 3 H), 1.48 (s, 3 H), 1.25 (s, 3 H), 0.65 (s,
3 H).
13C NMR: d = 214.1 (C), 169.9 (CH), 153.5 (C), 152.1 (C), 133.4
(CH), 128.0 (C), 115.8 (CH), 111.8 (CH), 110.8 (CH), 55.4 (CH3),
55.2 (CH3), 54.8 (C), 50.7 (C), 25.6 (2 C, CH3), 20.1 (CH3).
4-(2,5-Dimethoxyphenyl)-4-methylcyclopent-2-en-1-ol (25)
To a magnetically stirred soln of a 1:1 diastereomeric mixture of 18
(205 mg, 0.78 mmol) in anhyd CH2Cl2 (58 mL) was added a soln of
Grubbs’ catalyst PhCH=Ru(PCy3)2Cl2 (32 mg, 5 mol%) in anhyd
CH2Cl2 (20 mL) and the mixture was stirred at r.t. for 1 h. Evapora-
tion of the solvent under reduced pressure and column chromatog-
raphy (silica gel, EtOAc–hexane, 1:10–1:5) furnished a 1:1
diastereomeric mixture of 25 (170 mg, 93%) as an oil.
MS: m/z (%) = 260 (M+, 38), 246 (15), 245 (100), 230 (11), 215 (6),
202 (4), 123 (7).
HRMS: m/z [M + Na] calcd for C16H20NaO3: 283.1310; found:
283.1325.
IR (neat): 3392, 1607, 1585, 1496, 1417, 1282, 1222, 1179, 1114,
1067, 1049, 1028, 873, 801, 728 cm–1.
3-(2,5-Dimethoxyphenyl)-2,2,3-trimethylcyclopentanone (27)
To activated 10% Pd/C (30 mg) was added a soln of 17 (110 mg,
0.42 mmol) in EtOH (2 mL) and the mixture was stirred at r.t. for 1
h under an atmosphere of H2 created by evacuative replacement of
air (balloon). The catalyst was then filtered off using a small column
(silica gel). Evaporation of the solvent furnished 27 (105 mg, 96%)
as an oil.
1H NMR: d (mixture of diastereomers) = 6.80–6.55 (m, 3 H), 6.19
(d, J = 5.4 Hz, 1 H), 5.84 (m, 1 H), 4.82 and 4.70 (m, 1 H), 3.78 (s,
3 H), 3.73 and 3.71 (s, 3 H), 2.60 (dd, J = 14.4, 7.2 Hz) and 2.52 (dd,
J = 10.1, 7.5 Hz) [1 H], 2.03 (dd, J = 14.4, 3.9 Hz) and 1.92 (dd,
J = 14.1, 4.2 Hz) [1 H], 1.65 (br s, 1 H), 1.50 and 1.38 (s, 3 H).
13C NMR: d (mixture of diastereomers) = 153.4 and 153.2 (C),
151.9 and 151.5 (C), 142.4 (CH), 138.6 and 138.1 (C), 132.1 and
131.9 (CH), 113.8 and 113.7 (CH), 112.4 and 112.0 (CH), 110.5
and 110.3 (CH), 77.3 and 77.2 (CH), 55.7 and 55.5 (CH3), 55.4
(CH3), 51.7 and 50.4 (C), 49.2 and 48.5 (CH2), 29.2 and 27.9 (CH3).
IR (neat): 1736, 1608, 1587, 1497, 1465, 1372, 1285, 1226, 1181,
1090, 1050, 1027, 867, 801, 753, 721 cm–1.
1H NMR: d = 6.89 (d, J = 3.0 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H),
6.66 (dd, J = 8.7, 3.0 Hz, 1 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 2.55–2.35
(m, 3 H), 2.05–1.95 (m, 1 H), 1.38 (s, 3 H), 1.21 (s, 3 H), 0.66 (s, 3
H).
MS: m/z (%) = 234 (M+, 61), 219 (100), 204 (7), 191 (14), 177 (12),
175 (12), 161 (16) 115 (10).
HRMS: m/z [M + Na] calcd for C14H18NaO3: 257.1154; found:
257.1161.
13C NMR: d = 221.8 (C), 153.4 (C), 152.4 (C), 136.3 (C), 115.9
(CH), 111.4 (CH), 110.1 (CH), 55.4 (CH3), 54.7 (CH3), 52.6 (C),
48.9 (C), 34.4 (CH2), 32.7 (CH2), 23.5 (CH3), 21.9 (CH3), 21.8
(CH3).
MS: m/z (%) = 262 (M+, 83), 247 (14), 213 (10), 192 (28), 191
(100), 178 (28), 177 (22), 163 (28), 161 (22), 149 (10), 135 (10),
121 (14), 105 (8).
4-(2,5-Dimethoxyphenyl)-4-methylcyclopent-2-enone (26)
To a magnetically stirred soln of PCC (382 mg, 1.78 mmol) and
NaOAc (236 mg, 2.84 mmol) in CH2Cl2 (3 mL) was added a soln of
25 (165 mg, 0.71 mmol) in CH2Cl2 (2 mL). The mixture was stirred
at r.t. for 1 h and filtered through a column (silica gel, excess
CH2Cl2). Evaporation of the solvent furnished 26 (152 mg, 93%).
HRMS: m/z [M + Na] calcd for C16H22NaO3: 285.1467; found:
285.1472.
IR (neat): 1715, 1588, 1498, 1370, 1341, 1285, 1230, 1178, 1086,
1044, 1025, 932, 897, 869, 804, 729 cm–1.
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York

1532
A. Srikrishna et al.
PAPER
7-(2,5-Dimethoxyphenyl)-6,6,7-trimethyl-1,4-dithia-
spiro[4.4]nonane (28)
(CH), 59.5 and 59.4 (CH2), 55.7 and 55.6 (CH3), 55.4 and 55.3
(CH3), 50.7 and 50.5 (CH), 46.4 (C), 32.7 and 32.4 (CH2), 19.9 and
19.8 (CH3), 14.2 and 14.1 (CH3).
MS: m/z (%) = 318 (M+, 8), 191 (100), 176 (7), 161 (10), 160 (10),
To a magnetically stirred soln of 27 (100 mg, 0.38 mmol) in anhyd
CH2Cl2 (0.22 mL) was added ethane-1,2-dithiol (0.32 mL, 3.8
mmol) and I2 (20 mg, 25 mol%) and the mixture was stirred at r.t.
for 1 h. Then 1 M aq Na2S2O3 (1 mL) was added followed by 10%
aq NaOH (5 mL) and the mixture was stirred for 5 min. It was ex-
tracted with CH2Cl2 (2 × 3 mL) and the extracts were washed with
brine and dried (Na2SO4). Evaporation of the solvent and column
chromatography (silica gel, CH2Cl2–hexane, 1:9) furnished 28 (105
mg, 81%) as an oil.
149 (8), 121 (10).
HRMS: m/z [M + Na] calcd for C19H26NaO4: 341.1729; found:
341.1730.
Ethyl 2-(2,5-Dimethoxyphenyl)-2-methylcyclopent-3-ene-
carboxylate (31)
To a magnetically stirred soln of a 1:1 diastereomeric mixture of 30
(300 mg, 0.95 mmol) in anhyd CH2Cl2 (60 mL) was added a soln of
Grubbs’ catalyst PhCH=Ru(PCy3)2Cl2 (40 mg, 5 mol%) in anhyd
CH2Cl2 (10 mL) and the mixture was stirred at r.t. for 5 h. Evapora-
tion of the solvent under reduced pressure and column chromatog-
raphy (silica gel, EtOAc–hexane, 1:30) furnished a 1:1 diastereo-
meric mixture of 31 (265 mg, 97%) as an oil. Small samples of pure
cis- and trans-isomers were separated by careful column chroma-
tography (silica gel).
IR (neat): 1581, 1493, 1465, 1410, 1378, 1281, 1220, 1179, 1048,
1036, 1025, 867, 799, 727 cm–1.
1H NMR: d = 6.85 (d, J = 3.0 Hz, 1 H), 6.72 (d, J = 9.0 Hz, 1 H),
6.62 (dd, J = 9.0, 3.0 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.30–3.10
(m, 4 H), 2.85–2.40 (m, 2 H), 2.30 (m, 1 H), 1.73–1.63 (m, 1 H),
1.53 (s, 3 H), 1.25 (s, 3 H), 0.74 (s, 3 H).
MS: m/z (%) = 338 (M+, 7), 324 (4), 278 (4), 263 (4), 220 (11), 207
(33), 178 (100), 163 (26), 151 (16), 131 (10).
HRMS: m/z [M + H] calcd for C18H27O2S2: 339.1452; found:
339.1464.
trans-Isomer
IR (neat): 1730, 1585, 1497, 1464, 1419, 1370, 1341, 1280, 1228,
1179, 1049, 801, 724 cm–1.
1,4-Dimethoxy-2-(1,2,2-trimethylcyclopentyl)benzene (29)
To a magnetically stirred soln of 28 (36 mg, 0.107 mmol) in anhyd
EtOH (3 mL) was added Raney nickel (100 mg, excess) and the
mixture was refluxed for 5 h. It was then cooled and filtered through
a short column (silica gel, excess CH2Cl2). Evaporation of the sol-
vent furnished 29 (26 mg, 100%) as an oil.
1H NMR: d = 6.88 (d, J = 3.0 Hz, 1 H), 6.76 (d, J = 8.7 Hz, 1 H),
6.67 (dd, J = 8.7, 3.0 Hz, 1 H), 5.80 (dt, J = 5.7, 1.8 Hz, 1 H), 5.72
(dt, J = 5.7, 2.1 Hz, 1 H), 4.17 and 4.11 (2 dq, J = 10.8, 7.2 Hz, 2
H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.44 (dd, J = 8.7, 6.9 Hz, 1 H), 2.77
(ddt, J = 16.5, 7.2, 2.1 Hz, 1 H), 2.56 (ddt, J = 16.5, 5.7, 2.1 Hz, 1
H), 1.39 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 174.3 (C), 153.3 (C), 152.0 (C), 138.5 (CH), 137.1
(C), 126.8 (CH), 114.7 (CH), 112.1 (CH), 110.9 (CH), 59.8 (CH2),
55.4 (2 C, CH3), 54.5 (C), 51.9 (CH), 35.4 (CH2), 22.1 (CH3), 14.5
(CH3).
IR (neat): 1585, 1493, 1465, 1415, 1371, 1282, 1224, 1179, 1055,
1030, 797, 726 cm–1.
1H NMR: d = 6.85 (d, J = 3.0 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H),
6.60 (dd, J = 8.4, 3.0 Hz, 1 H), 3.73 (s, 6 H), 2.60–2.40 (m, 1 H),
1.80–1.40 (m, 5 H), 1.34 (s, 3 H), 1.13 (s, 3 H), 0.69 (s, 3 H).
13C NMR: d = 153.2 (2 C, C), 137.5 (C), 116.4 (CH), 112.0 (CH),
109.8 (CH), 55.4 (CH3), 55.3 (CH3), 51.5 (C), 44.4 (C), 42.1 (CH2),
40.0 (CH2), 27.7 (CH3), 26.1 (CH3), 23.2 (CH3), 20.7 (CH2).
MS: m/z (%) = 290 (M+, 60), 229 (100), 217 (24), 216 (21), 201
(65), 191 (38), 188 (31), 185 (35), 175 (25), 165 (36), 161 (25), 138
(24), 115 (36).
HRMS: m/z [M + Na] calcd for C17H22NaO4: 313.1416; found:
313.1414.
HRMS: m/z [M + Na] calcd for C16H24NaO2: 271.1674; found:
271.1678.
cis-Isomer
Ethyl 2-Allyl-3-(2,5-dimethoxyphenyl)-3-methylpent-4-enoate
(30)
IR (neat): 1730, 1606, 1587, 1498, 1419, 1369, 1342, 1282, 1228,
1180, 1097, 1065, 1048, 871, 801, 730 cm–1.
To a cold (–70 °C) magnetically stirred soln of i-Pr2NH (0.39 mL,
2.79 mmol) in anhyd THF (4 mL) was added a 2.35 M n-BuLi in
hexane (1.1 mL, 2.52 mmol) and the mixture was stirred for 10 min.
To LDA thus formed was added dropwise a soln of 23 (350 mg,
1.26 mmol) in anhyd THF (3 mL) and the mixture was stirred for 40
min. Allyl bromide (0.16 mL, 1.9 mmol) was added to the mixture
and it was stirred at r.t. for 4 h. The mixture was then diluted with
H2O and extracted with Et2O (3 × 4 mL). The combined Et2O ex-
tracts were washed with 3 M aq HCl, sat. aq NaHCO3, and brine and
dried (Na2SO4). Evaporation of the solvent and column chromatog-
raphy (silica gel, EtOAc–hexane, 1:20) furnished a 1:1 diastereo-
meric mixture of 30 (335 mg, 84%).
1H NMR: d = 6.82 (d, J = 2.7 Hz, 1 H), 6.67 (d, J = 9.0 Hz, 1 H),
6.62 (dd, J = 9.0, 2.7 Hz, 1 H), 5.93–5.85 (m, 1 H), 5.73 (dt, J = 5.4,
2.1 Hz, 1 H), 3.72 (s, 3 H), 3.71 (s, 3 H), 3.80–3.55 (m, 2 H), 3.30
(dd, J = 7.8, 4.5 Hz, 1 H), 2.80–2.59 (m, 2 H), 1.52 (s, 3 H), 0.83 (t,
J = 7.2 Hz, 3 H).
13C NMR: d = 174.1 (C), 153.1 (C), 151.9 (C), 137.7 (CH), 134.5
(C), 127.1 (CH), 115.0 (CH), 111.2 (CH), 111.0 (CH), 59.4 (CH2),
55.8 (C), 55.4 (CH3), 55.1 (CH3), 53.7 (CH), 36.5 (CH2), 28.2
(CH3), 13.8 (CH3).
MS: m/z (%) = 290 (M+, 52), 275 (8), 229 (100), 201 (62), 187 (23),
165 (22), 138 (19), 115 (29).
IR (neat): 1727, 1640, 1608, 1584, 1495, 1465, 1373, 1350, 1280,
1227, 1181, 1049, 1027, 916, 804, 731 cm–1.
1H NMR: d (1:1 mixture of diastereomers) = 6.76–6.45 (m, 4 H),
5.75–5.55 (m, 1 H), 5.15–4.85 (m, 4 H), 4.00–3.60 (m, 3 H), 3.82
(s, 3 H), 3.71 (s, 3 H), 2.50–2.20 (m, 1 H), 2.10–1.80 (m, 1 H), 1.52
and 1.51 (s, 3 H), 1.02 and 0.91 (t, J = 7.2 Hz, 3 H).
13C NMR: d (1:1 mixture of diastereomers) = 173.8 and 173.4 (C),
153.4 and 153.2 (C), 152.4 and 152.2 (C), 143.6 and 143.4 (CH),
136.6 and 136.5 (CH), 135.1 and 135.0 (C), 116.0 (CH2), 115.7 and
115.1 (CH), 113.3 and 113.1 (CH2), 112.3 (CH), 111.1 and 111.0
HRMS: m/z [M + Na] calcd for C17H22NaO4: 313.1416; found:
313.1411.
Ethyl cis-2-(2,5-Dimethoxyphenyl)-1,2-dimethylcyclopent-3-
enecarboxylate (32)
To a cold (–30 °C) magnetically stirred soln of LDA [prepared from
i-Pr2NH (0.22 mL, 1.55 mmol) and a soln of 2.3 M n-BuLi in hex-
ane (0.57 mL, 1.30 mmol) in anhyd THF (3 mL)] was added drop-
wise a soln of 31 (150 mg, 0.517 mmol) in a mixture of anhyd THF
(1 mL) and anhyd HMPA (2.5 mL) and stirred at this temperature
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Herbertenones A and B
1533
for 40 min. MeI (0.1 mL, 1.55 mmol) was added to the mixture and
it was stirred at r.t. for 7 h. The mixture was diluted with H2O (5
mL) and extracted with Et2O (3 × 4 mL). The combined Et2O layers
were washed with 3 M aq HCl (5 mL), sat. aq NaHCO3 soln (5 mL),
and brine, and dried (Na2SO4). Evaporation of the solvent and col-
umn chromatography (silica gel, EtOAc–hexane, 1:20) furnished 32
(138 mg, 88%) as an oil.
MS: m/z (%) = 264 (M+, 59), 191 (19), 178 (30), 166 (30), 165
(100), 151 (28), 135 (24), 121 (17).
HRMS: m/z [M + Na] calcd for C16H24NaO3: 287.1623; found:
287.1609.
cis-2-(2,5-Dimethoxyphenyl)-1,2-dimethylcyclopentane-
carbaldehyde (35)
IR (neat): 1723, 1586, 1498, 1416, 1378, 1282, 1228, 1198, 1180,
1113, 1060, 1042, 1028, 799, 736 cm–1.
Oxidation of 34 (85 mg, 0.322 mmol) with PCC (208 mg, 0.97
mmol) and silica gel (208 mg) in CH2Cl2 (1 mL) at r.t. for 30 min,
followed by column chromatography (silica gel, EtOAc–hexane,
1:20) furnished 35 (78 mg, 92%) as an oil.
1H NMR: d = 6.76 (d, J = 3.0 Hz, 1 H), 6.68 (d, J = 8.7 Hz, 1 H),
6.61 (dd, J = 8.7, 3.0 Hz, 1 H), 5.80–5.70 (m, 2 H), 3.74 (s, 3 H),
3.71 (s, 3 H), 3.43, 3.34 (2 dq, J = 10.8, 7.5 Hz, 2 H), 3.01 and 2.26
(2 d, J = 16.5 Hz, 2 H), 1.50 (s, 3 H), 1.49 (s, 3 H), 0.81 (t, J = 7.5
Hz, 3 H).
13C NMR: d = 176.2 (C), 153.1 (C), 153.0 (C), 139.1 (CH), 135.1
(C), 127.2 (CH), 115.9 (CH), 111.7 (CH), 111.3 (CH), 59.6 (CH2),
59.0 (2 C, C), 55.5 (CH3), 55.3 (CH3), 46.4 (CH2), 23.3 (CH3), 21.5
(CH3), 13.7 (CH3).
IR (neat): 2721, 1717, 1608, 1586, 1497, 1463, 1377, 1284, 1226,
1180, 1052, 1027, 917, 878, 803, 729 cm–1.
1H NMR: d = 9.00 (s, 1 H), 6.81 (d, J = 2.7 Hz, 1 H), 6.69 (d, J = 8.7
Hz, 1 H), 6.64 (dd, J = 8.7, 2.7 Hz, 1 H), 3.73 (s, 3 H), 3.68 (s, 3 H),
2.38 (dt, J = 12.6, 8.1 Hz, 1 H), 2.05–1.75 (m, 4 H), 1.55–1.43 (m,
1 H), 1.32 (s, 3 H), 1.27 (s, 3 H).
13C NMR: d = 203.6 (CH), 153.5 (C), 151.7 (C), 135.2 (C), 115.3
(CH), 111.4 (CH), 110.7 (CH), 57.6 (C), 55.3 (CH3), 54.7 (CH3),
50.9 (C), 41.2 (CH2), 36.9 (CH2), 24.3 (CH3), 22.2 (CH2), 17.9
(CH3).
MS: m/z (%) = 304 (M+, 58), 231 (23), 227 (27), 215 (22), 203 (34),
202 (100), 199 (43), 191 (55), 190 (82), 187 (55), 175 (44), 161
(32), 139 (72), 115 (52).
HRMS: m/z [M + Na] calcd for C18H24NaO4: 327.1572; found:
MS: m/z (%) = 262 (M+, 30), 192 (33), 191 (100), 161 (10), 149
327.1559.
(10), 135 (6), 121 (15).
HRMS: m/z [M + Na] calcd for C16H22NaO3: 285.1467; found:
285.1459.
Ethyl cis-2-(2,5-Dimethoxyphenyl)-1,2-dimethylcyclopentane-
carboxylate (33)
Catalytic hydrogenation of 32 (115 mg, 0.38 mmol) with activated
10% Pd/C (25 mg) in EtOH (3 mL) at 1 bar of H2 at r.t. for 2 h fur-
nished 33 (115 mg, 99%) as an oil.
1,4-Dimethoxy-2-(1,2,2-trimethylcyclopentyl)benzene (29)
A soln of 35 (78 mg, 0.30 mmol) and hydrazine hydrate (0.15 mL,
3.0 mmol) in diethylene glycol (2 mL) was heated to 125 °C for 3 h
in a sealed tube and then cooled to r.t. KOH (168 mg, 3.0 mmol) was
added to the mixture and it was heated to 200 °C for 12 h. The mix-
ture was then cooled to r.t., acidified with 3 M aq HCl (5 mL) and
extracted with CH2Cl2 (3 × 2 mL). The combined CH2Cl2 extracts
were washed with brine and dried (Na2SO4). Evaporation of the sol-
vent and column chromatography (silica gel, CH2Cl2–hexane, 1:20)
furnished 29 (61 mg, 82%), which exhibited TLC and spectral data
(IR, 1H and 13C NMR) identical to the sample obtained earlier.
IR (neat): 1723, 1609, 1586, 1498, 1380, 1366, 1285, 1226, 1180,
1141, 1103, 1054, 1029, 870, 802, 725 cm–1.
1H NMR: d = 6.81 (d, J = 3.0 Hz, 1 H), 6.67 (d, J = 8.7 Hz, 1 H),
6.59 (dd, J = 8.7, 3.0 Hz, 1 H), 3.72 (s, 3 H), 3.69 (s, 3 H), 3.75–3.50
(m, 2 H), 2.70–2.50 (m, 1 H), 2.24 (dt, J = 12.0, 9.3 Hz, 1 H), 1.95–
1.60 (m, 4 H), 1.44 (s, 3 H), 1.32 (s, 3 H), 0.82 (t, J = 7.2 Hz, 3 H).
13C NMR: d = 177.3 (C), 153.2 (C), 152.3 (C), 138.0 (C), 114.9
(CH), 111.5 (CH), 110.3 (CH), 59.6 (CH2), 55.6 (CH3), 55.1 (CH3),
52.4 (2 C, C), 41.2 (CH2), 40.7 (CH2), 24.0 (CH3), 21.9 (CH3), 22.0
(CH2), 13.8 (CH3).
MS: m/z (%) = 306 (M+, 95), 232 (16), 204 (13), 193 (34), 192
(100), 179 (34), 173 (43), 165 (35), 163 (29), 161 (30), 151 (40),
115 (71).
4,4¢-Bis(1,2,2-trimethylcyclopentyl)bi(cyclohexa-1,4-dienyl)-
3,3¢,6,6¢-tetrone (37)
To a magnetically stirred soln of 29 (17 mg, 0.07 mmol) in MeCN
(1 mL) and H2O (1 mL) was added CAN (77 mg, 0.14 mmol). The
mixture was stirred at r.t. for 1 h and extracted with CH2Cl2 (3 × 3
mL). The combined CH2Cl2 layers were washed with brine and
dried (Na2SO4). Evaporation of the solvent and column chromatog-
raphy (silica gel, EtOAc–hexane, 1:10) furnished 37 (8 mg, 53%) as
yellow oil.
HRMS: m/z [M + Na] calcd for C18H26NaO4: 329.1729; found:
329.1731.
cis-2-(2,5-Dimethoxyphenyl)-1,2-dimethylcyclopentane-
methanol (34)
Reduction of 33 (110 mg, 0.36 mmol) with LAH (27 mg, 0.72
mmol) in Et2O (3 mL) at –20 °C for 30 min, with purification by
column chromatography (silica gel, EtOAc–hexane, 1:19) fur-
nished 34 (88 mg, 93%) as an oil.
IR (neat): 1655, 1589, 1462, 1386, 1371, 1347, 1305, 1291, 1091,
1019, 927, 831, 790 cm–1.
1H NMR: d = 6.79 (s, 2 H), 6.70 (s, 2 H), 2.20–2.35 (m, 2 H), 1.50–
1.80 (m, 10 H), 1.32 (s, 6 H), 1.14 (s, 6 H), 0.79 (s, 6 H).
HRMS: m/z [M + K] calcd for C28H34KO4: 473.2130; found:
473.2094.
IR (neat): 3446, 1608, 1585, 1491, 1465, 1414, 1376, 1283, 1223,
1179, 1040, 1026, 872, 801, 726 cm–1.
1H NMR: d = 6.81 (d, J = 3.0 Hz, 1 H), 6.76 (d, J = 9.0 Hz, 1 H),
6.63 (dd, J = 9.0, 3.0 Hz, 1 H), 3.76 (s, 3 H), 3.71 (s, 3 H), 3.04 (s,
2 H), 2.45–2.30 (m, 1 H), 2.00 (br s, 1 H), 1.85–1.50 (m, 4 H), 1.36–
1.23 (m, 1 H), 1.38 (s, 3 H), 1.15 (s, 3 H).
13C NMR: d = 153.7 (C), 152.6 (C), 137.0 (C), 116.2 (CH), 112.7
(CH), 110.4 (CH), 70.3 (CH2), 55.8 (CH3), 55.3 (CH3), 50.7 (C),
49.1 (C), 42.1 (CH2), 37.0 (CH2), 24.2 (CH3), 21.3 (CH2), 21.0
(CH3).
2-(1,2,2-Trimethylcyclopentyl)benzene-1,4-diol (38)
To a cold (–40 °C) magnetically stirred soln of 29 (74 mg, 0.3
mmol) in anhyd CH2Cl2 (1 mL) was added dropwise 1 M BBr3 in
CH2Cl2 (0.8 mL, 0.8 mmol) and the mixture was stirred at this tem-
perature for 30 min and then stirred at r.t. for 5 h. The mixture was
then quenched with sat. aq NaHCO3 soln (4 mL) and extracted with
CH2Cl2 (3 × 2 mL). The combined CH2Cl2 extracts were washed
with brine and dried (Na2SO4). Evaporation of the solvent and col-
umn chromatography (silica gel, EtOAc–hexane, 1: 20) furnished
38 (66 mg, 98%).
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York

1534
A. Srikrishna et al.
PAPER
IR (neat): 3318, 1651, 1592, 1508, 1445, 1386, 1372, 1294, 1200,
1140, 1056, 939, 872, 806, 769 cm–1.
1H NMR: d = 6.77 (s, 1 H), 6.51 (s, 2 H), 4.44 (br s, 1 H), 4.38 (br
s, 1 H), 2.60–2.40 (m, 1 H), 1.81–1.50 (m, 5 H), 1.39 (s, 3 H), 1.16
(s, 3 H), 0.76 (s, 3 H).
13C NMR: d = 148.63 (C), 148.57 (C), 134.9 (C), 117.5 (CH), 116.6
(CH), 113.2 (CH), 51.1 (C), 44.7 (C), 41.2 (CH2), 39.4 (CH2), 27.0
(CH3), 25.6 (CH3), 22.8 (CH3), 20.3 (CH2).
13C NMR: d (2:1 mixture of 13 and 14) = 185.8 (C), 148.8 and 148.7
(CH), 148.1 and 147.8 (CH), 142.59 and 142.57 (C), 129.2 and
129.0 (CH), 68.1 and 67.8 (C), 50.41 and 50.39 (C), 43.7 and 43.5
(C), 41.62 and 41.56 (CH2), 38.7 and 38.6 (CH2), 27.6 and 27.7
(CH3), 27.5 and 27.4 (CH3), 25.53 and 25.46 (CH3), 22.4 and 22.7
(CH3).
Acknowledgment
MS: m/z (%) = 220 (M+, 48), 163 (14), 150 (61), 149 (32), 138 (38),
137 (100), 135 (32), 123 (30), 107 (21).
We thank Prof. Asakawa for providing the copies of the NMR and
Mass spectra of natural herbertenones. We are grateful to the CSIR
and DBT, New Delhi for the financial support.
HRMS: m/z [M + Na] calcd for C14H20NaO2: 243.1361; found:
243.1375.
References
2-(1,2,2-Trimethylcyclopentyl)-1,4-benzoquinone (36)
To a magnetically stirred soln of 38 (30 mg, 0.14 mmol) in MeCN
(3 mL) and H2O (3 mL) was added CAN (230 mg, 0.42 mmol). The
mixture was stirred at r.t. for 1 h. Workup as described for 37, fol-
lowed by column chromatography (silica gel, EtOAc–hexane, 1:10)
furnished 36 (30 mg, 100%) as yellow oil.
(1) 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.
(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. (g) Feld, H.; Zapp, J.; Becker, H. Phytochemistry
2003, 64, 1335.
IR (neat): 1654, 1589, 1462, 1372, 1347, 1306, 1292, 1091, 1019,
927, 832, 788 cm–1.
1H NMR: d = 6.65 (s, 2 H), 6.62 (s, 1 H), 2.35–2.15 (m, 1 H), 1.80–
1.45 (m, 5 H), 1.29 (s, 3 H), 1.12 (s, 3 H), 0.74 (s, 3 H).
13C NMR: d = 187.7 (C), 187.6 (C), 154.9 (C), 138.7 (CH), 134.6
(CH), 133.9 (CH), 51.6 (C), 44.2 (C), 41.6 (CH2), 38.6 (CH2), 28.0
(CH3), 25.4 (CH3), 23.0 (CH3), 20.0 (CH2).
MS: m/z (%) = 218 (M+, 5), 203 (20), 189 (2), 175 (44), 161 (24),
150 (100), 147 (25), 137 (28), 135 (25), 108 (14), 91 (40).
(5) Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y.
Phytochemistry 2000, 55, 247.
HRMS: m/z [M + Na] calcd for C14H18NaO2: 241.1204; found:
241.1214.
(6) (a) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M.
Org. Lett. 2006, 8, 3379. (b) Ray, D.; Ray, J. K. Org. Lett.
2007, 9, 191. (c) Srikrishna, A.; Ravikumar, P. C. Synthesis
2007, 65. (d) Srikrishna, A.; Satyanarayana, G. Tetrahedron
2006, 62, 2892; and references cited therein.
(7) (a) Srikrishna, A.; Ramasastry, S. S. V. Tetrahedron Lett.
2005, 46, 7373. (b) Srikrishna, A.; Lakshmi, B. V.
Tetrahedron Lett. 2005, 46, 7029. (c) Srikrishna, A.;
Lakshmi, B. V.; Mathews, M. Tetrahedron Lett. 2006, 47,
2103.
(8) (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.
(9) 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.
UV: l = 307, 269.5 nm.
4-Hydroxy-4-methyl-2-(1,2,2-trimethylcyclopentyl)cyclohexa-
2,5-dienone (Herbertenones A and B, 13 and 14)
To a cold magnetically stirred soln of 36 (25 mg, 0.115 mmol) at –
30 °C in anhyd THF (4 mL) was added 0.5 M MeMgBr in THF (0.5
mL, 0.25 mmol) dropwise over a period of 2 min. It was stirred for
1 min, the reaction was quenched with cold sat. aq NH4Cl (4 mL)
and extracted with Et2O (3 × 3 mL). Evaporation of the solvent and
column chromatography (silica gel, EtOAc–hexane, 1:12) fur-
nished a 2:1 mixture of herbertenone A (13) and herbertenone B
(14) (18 mg, 67%) as an oil.
IR (neat): 3396, 1665, 1629, 1463, 1387, 1370, 1257, 1127, 1055,
1020, 899, 835, 736 cm–1.
1H NMR: d (2:1 mixture of 13 and 14) = 6.76 (dd, J = 9.6, 3 Hz, 1
H), 6.71 (d, J = 3 Hz, 1 H), 6.03 (d, J = 9.6 Hz, 1 H), 2.40–2.17 (m,
1 H), 1.96 and 2.03 (br s, 1 H), 1.75–1.50 (m, 5 H), 1.46 (s, 3 H),
1.25 and 1.27 (s, 3 H), 1.13 and 1.11 (s, 3 H) and 0.72 (s, 3 H).
(10) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem.
2001, 66, 7527.
(11) (a) Ho, T. L. Synth. Commun. 1979, 9, 237. (b) Jacob, P.;
Callery, P. S.; Shulgin, A. T.; Castagnoli, N. J. Org. Chem.
1976, 41, 3627.
Synthesis 2008, No. 10, 1527–1534 © Thieme Stuttgart · New York