A Formal Total Synthesis of (±)-1,13-Herbertenediol

Article abstract of DOI:10.1002/ejoc.200300589

A formal total synthesis of (±)-1,13-herbertenediol, employing a ring-closing metathesis reaction of the 4-arylhepta-1,6-diene-4-carboxylate 15 as the key reaction, is described. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300589

FULL PAPER
A Formal Total Synthesis of (؎)-1,13-Herbertenediol
Adusuhilli Srikrishna*[a] and M. Srinivasa Rao[a]
Keywords: Terpenoids / Synthesis design / Metathesis / Rearrangement
A formal total synthesis of ( )-1,13-herbertenediol, em-
ploying a ring-closing metathesis reaction of the 4-arylhepta-
1,6-diene-4-carboxylate 15 as the key reaction, is described.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
The sesquiterpenes cuparanes and herbertanes are inter-
esting synthetic targets owing to the presence of a sterically
crowded 1-aryl-1,2,2-trimethylcyclopentane moiety, and the
difficulty associated with the construction of vicinal quater-
nary carbon atoms on a cyclopentane ring. The significant
biological properties of the phenolic herbertanes make them
important synthetic targets of current interest.[3] Since its
isolation, there are two reports on the synthesis of 1,13-
herbertenediol (3). In 2001, Fukuyama et al., reported the
first synthesis employing an intramolecular Heck reac-
tion.[4] Recently,[3g] we have reported the synthesis of 1,13-
herbertenediol (3) along with α- and β-herbertenols (1b)
and (1d) employing orthoester Claisen rearrangement as the
key reaction for the creation of the two vicinal quaternary
carbon atoms. Herein we wish to describe an alternate strat-
egy for the synthesis of 1,13-herbertenediol ((Ϯ)-3).
Herbertanes are a small group of sesquiterpenes, which
are considered as chemical markers for the liverworts be-
longing to the genus Herbertus.[1a] Isolation of the first
members of the herbertane group 1aϪe and 2a from H.
adunca was reported earlier by Matsuo and co-workers.[1b]
Subsequently,[1c] Rycroft et al. reported the isolation of the
aldehyde 1f and the ester 1g from H.s aduncus. Recently,[1a]
Asakawa and co-workers reported the isolation from the
Japanese liverwort H. sakuraii of seven new members of this
group: herbertenelactol (2b), 1,13-herbertenediol (3), 1,14-
herbertenediol (4), 1,15-herbertenediol (5), herbertenones A
and B (6a,b) and 12-methoxyherbertenediol (7) along with
dimeric herbertanes mastigophorenes AϪC. The phenolic
herbertanes, e.g. 1bϪd and the dimeric mastigophorenes
have been shown to possess interesting biological properties
such as growth-inhibiting, antifungal, antilipid peroxidation
and neurotropic activities.[1,2]
Scheme 1
Initially we envisioned (Scheme 1) that Ireland ester
Claisen rearrangement[5] of ester 8 (or rearrangement of 8a
and subsequent allylation) followed by a ring-closing met-
athesis (RCM) reaction[6] of the resulting diene 9 would
generate the cyclopentene carboxylate 10 containing the
requisite two vicinal quaternary carbon atoms, which could
be transformed into 1,13-herbertenediol (3). The arylacetic
acid 11 required for the generation of ester 8a could be
obtained from allyl 4-methylphenyl ether via Claisen re-
[a]
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
Fax: (internat.) ϩ 91-80-3600683 or -3600529
E-mail: ask@orgchem.iisc.ernet.in
Eur. J. Org. Chem. 2004, 499Ϫ503
DOI: 10.1002/ejoc.200300589
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
499

A. Srikrishna, M. S. Rao
FULL PAPER
arrangement followed by oxidative cleavage of the allyl
group.
Accordingly, we started by preparing allylanisole (12)
from allyl 4-methylphenyl ether in a straightforward man-
ner via thermolysis followed by etherification. Ozonolytic
cleavage of allylanisole (12) followed by oxidation of the
resulting aldehyde with Jones reagent generated the aryla-
cetic acid 11, which on esterification furnished ester 11a
(Scheme 2).[7]
Scheme 3. Reagents, conditions and yields: (a) LDA, THF, Ϫ70 °C;
CH2ϭCHCH2Br, Ǟ room temp., 4 h; 92%; (b) LDA, THF, HMPT,
Ϫ70 °C; CH2ϭCHCH2Br, Ǟ room temp., 8 h; 86%; (c) 5 mol %
[PhCHϭRuCl2(PCy3)2], CH2Cl2, room temp., 4 h, 95%; (d) PDC,
py, 100 °C, 8 h, 65%; (e) NaH, DME, MeI, room temp., 12 h, 71%;
(f) H2 (1 atm), 5% Pd/C, EtOH, 2 h, 90%; (g) (CH2SH)2, BF3·Et2O,
C6H6, 0 °C Ǟ room temp., 4 h, 83%; (h) Raney Ni, EtOH, reflux,
3 h, 85%; (i) BBr3, CH2Cl2, Ϫ40 °C Ǟ room temp., 4 h, 65%; (j)
ref.[4]
Scheme 2. Reagents, conditions and yields: (a) O3/O2, CH2Cl2/
MeOH (4:1); Me2S, 4 h; 86%; (b) Jones reagent, Me2CO, 0 °C Ǟ
room. temp., 2 h, 88%; (c) MeOH, H2SO4, reflux, 8 h, 90%; (d)
Me2CϭCHCH2OH, DCC, DMAP, CH2Cl2, 6 h, room temp., 88%;
(e) LDA, TBDMSCl; ∆
Coupling of 11 with 3-methylbut-2-enol in the presence
of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino-
)pyridine (DMAP) furnished ester 8a. To avoid steric
crowding during the [3,3]-sigmatropic shift, it was contem-
plated that the allylation could be carried out after the Ire-
land ester Claisen rearrangement of 8a. However, quite sur-
prisingly and contrary to our expectations, the enolate or
the corresponding silyl enol ether of 8a failed to undergo
the Claisen rearrangement to generate 13 under a variety of
conditions. Hence, the strategy was altered and it was de-
cided to create the second quaternary centre at a later stage.
The synthetic sequence is depicted in Scheme 3.
Sequential allylation of ester 11a with lithium diisopro-
pylamide (LDA) and allyl bromide generated the diallylated
ester 15 via ester 14, in 79% yield. RCM reaction of 15 in
dichloromethane with 5 mol% of first-generation Grubbs’
catalyst at room temperature furnished the cyclopen-
tenecarboxylate 16 in near quantitative yield. Allylic oxi-
dation of 16 with pyridinium dichromate (PDC) in pyridine
furnished enone 17 in a highly regioselective manner, whose
structure was deduced from its spectroscopic data, in par-
ticular from the two doublets at δ ϭ 6.34 and 7.75 ppm for
the α- and β-olefinic protons of the cyclopentenone moiety
the lactone 22, which exhibited the spectroscopic data (IR,
1H and 13C NMR) identical to that of an authentic sample.
Since lactone 22 has already been transformed into herbert-
ene-1,13-diol by lithium aluminium hydride reduction[4] the
present sequence constitutes a formal total synthesis of her-
bertene-1,13-diol ((Ϯ)-3).
In conclusion, we have developed a RCM-based method-
ology for the synthesis of 1,13-herbertenediol (3). Failure of
the Ireland ester Claisen rearrangement of ester 8a made
the sequence longer than anticipated. Currently, we are in-
vestigating the possibility of extension of this methodology
for other bioactive herbertenes and mastigophorenes.
Experimental Section
IR spectra were recorded with a Jasco FTIR 410 spectrophoto-
meter. 1H (300 MHz) and 13C (75 MHz) NMR spectra were re-
corded with a Jeol JNM λ-300 spectrometer. The chemical shifts
(δ ppm) and coupling constants (Hz) are reported in the standard
1
fashion with reference to either internal tetramethylsilane (for H)
or the central line (δ ϭ 77.0 ppm) of CDCl3 (for 13C). In the 13C
NMR spectra, the nature of the carbon atoms (C, CH, CH2 or
(it is well established that the other regioisomer would gen- CH3) was determined by recording the DEPT-135 spectrum, and
is given in parentheses. Low-resolution mass spectra were recorded
using a Shimadzu GCMS-QP5050A instrument using direct inlet
mode. Relative intensities are given in parentheses. High-resolution
mass spectra (HRMS) were recorded with a Micromass Q-Tof mic-
roTM instrument. Ozonolysis was carried out using a Fischer 502
ozone generator, whose parameters were adjusted to provide
1 mmol of ozone every four minutes. Hydrogenation at one atmos-
pheric pressure was carried out using a hydrogen-filled balloon.
Analytical thin-layer chromatography (TLC) was performed on
glass plates coated with Acme’s silica-gel G containing 13% calcium
erate two triplets of doublet signals for the cyclopentenone
olefinic protons). One-step dialkylation of 17 with sodium
hydride and methyl iodide in dimethoxyethane (DME) gen-
erated the second quaternary carbon atom to furnish enone
18, which on hydrogenation using 5% palladium over car-
bon as the catalyst furnished cyclopentanone 19. Thioket-
alisation of 19 with ethanedithiol and boron trifluoride eth-
erate followed by Raney nickel-mediated desulfurisation of
thioketal 20 furnished ester 21. Finally, boron tribromide-
mediated cleavage of the methyl ether transformed 21 into sulfate as binder, and various combinations of ethyl acetate and
500  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 499Ϫ503

A Formal Total Synthesis of ( )-1,13-Herbertenediol
FULL PAPER
hexane were used as eluent. Visualization of spots was ac-
silica-gel column using ethyl acetate. Evaporation of the solvent
complished by exposure to iodine vapour. Acme’s silica gel and purification of the residue over a silica-gel column using ethyl
(100Ϫ200 mesh) was used for column chromatography. All small- acetate/hexane (1:20) as eluent furnished the ester 8a (145 mg, 88%)
scale dry reactions were carried out using the standard syringe sep- as an oil. IR (neat): ν˜max. ϭ 1739, 1615, 1505, 1445, 1378, 1340,
1
tum technique. Dry THF was obtained by distillation over sodium/
benzophenone ketyl. Dry diethyl ether was obtained by distillation
over sodium and stored over sodium wire. Dry dichloromethane
was prepared by distillation over P2O5 or calcium hydride. Dry di-
isopropylamine was obtained by distillation over KOH and stored
over KOH.
1256, 1159, 1035, 973, 807 cmϪ1. H NMR (300 MHz, CDCl3
ϩ
CCl4): δ ϭ 1.70 (s, 3 H) and 1.76 (s, 3 H) [2 ϫ olefinic CH3], 2.27
(s, 3 H, ArCH3), 3.54 (s, 2 H, CH2CO), 3.77 (s, 3 H, OCH3), 4.56
(d, J ϭ 7.2 Hz, 2 H, OCH2), 5.32 (t of d, J ϭ 7.2, 1.5 Hz, 1 H,
olefinic H), 6.71 (d, J ϭ 8.1 Hz, 1 H, H-3Ј), 6.95 (s, 1 H, H-6Ј),
6.98 (d, J ϭ 8.1 Hz, 1 H, H-4Ј) ppm. 13C NMR (75 MHz, CDCl3
ϩ CCl4): δ ϭ 18.1 (CH3), 20.6 (CH3), 25.9 (CH3), 35.8 (CH2), 55.4
(CH3), 61.4 (CH2), 110.4 (CH), 119.2 (CH), 122.9 (C), 128.7 (CH),
129.4 (C), 131.7 (CH), 138.3 (C), 155.5 (C), 171.5 (C, OCϭO) ppm.
MS: m/z (%) ϭ 248 (25) [Mϩ], 180 (2), 149 (2), 136 (12), 135 (100),
122 (3), 105 (60), 91 (13), 79 (12), 69 (65). HRMS: m/z calcd. for
C15H20O3Na [M ϩ Na]: 271.1310, found 271.1301.
Methyl (2-Methoxy-5-methylphenyl)acetate (11a): A pre-cooled
(Ϫ78 °C) mixture of ozone in oxygen was passed through a cold
(Ϫ78 °C) solution of the methyl ether 12 (1.0 g, 6.17 mmol) and a
catalytic amount of NaHCO3 in methanol (2 mL) and CH2Cl2
(8 mL) for 24 min. The reaction mixture was flushed off with oxy-
gen, and dimethyl sulfide (1.80 mL, 24.7 mmol) was added to the
reaction mixture. This was then slowly warmed to room temp. and
magnetically stirred for 8 h. Evaporation of the solvent under re-
duced pressure and purification of the residue on a silica-gel col-
umn using ethyl acetate/hexane (1:10) as eluent furnished (2-meth-
oxy-5-methylphenyl)acetaldehyde (860 mg, 86%) as an oil: IR
(neat): ν˜max. ϭ 1725, 1612, 1504, 1462, 1252, 1230, 1130, 1033,
Methyl 2-(2-Methoxy-5-methylphenyl)pent-4-enoate (14): A solu-
tion of nBuLi (2.5  in hexane, 2.24 mL, 5.60 mmol) was slowly
added to a cold (Ϫ78 °C), magnetically stirred solution of diisopro-
pylamine (0.9 mL, 6.20 mmol) in anhydrous THF (3 mL) and
stirred for 10 min. A solution of 11a (600 mg, 3.10 mmol) in anhy-
drous THF (2 mL) was added dropwise to the LDA thus formed
and stirred for 40 min at the same temperature. The enolate was
treated with allyl bromide (0.52 mL, 6.20 mmol) and stirred for 3 h.
The reaction mixture was then diluted with water and extracted
with diethyl ether (3 ϫ 4 mL). The combined diethyl ether extract
was washed sequentially with 3  aqueous HCl, saturated aqueous
NaHCO3 solution and brine, and dried (Na2SO4). Evaporation of
the solvent and purification of the residue over a silica-gel column
using ethyl acetate/hexane (1:20) as eluent furnished the pentenoate
14 (665 mg, 92%) as an oil. IR (neat): ν˜max. ϭ 3076, 1736, 1641,
1611, 1503, 1462, 1438, 1348, 1247, 1168, 1121, 1033, 916, 808
1
809 cmϪ1. H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 2.27 (s, 3 H,
ArCH3), 3.56 (d, J ϭ 2.1 Hz, 2 H, CH2CHO), 3.78 (s, 3 H, OCH3),
6.75 (d, J ϭ 8.2 Hz, 1 H, H-3Ј), 6.91 (s, 1 H, H-6Ј), 7.02 (d, J ϭ
8.2 Hz, 1 H, H-4Ј), 9.62 (t, J ϭ 2.1 Hz, 1 H, CHO) ppm. 13C NMR
(75 MHz, CDCl3 ϩ CCl4): δ ϭ 20.4 (CH3), 45.4 (CH2), 55.3 (CH3),
110.3 (CH), 120.9 (C), 129.1 (CH), 129.9 (C), 132.0 (CH), 155.5
(C), 199.4 (CH, CHO) ppm. MS: m/z (%) ϭ 164 (5) [Mϩ], 163 (50),
152 (13), 149 (58), 135 (100), 121 (10), 105 (45), 91 (28)].
A
magnetically stirred solution of the aldehyde (800 mg,
4.88 mmol), obtained above, in acetone (3 mL) was treated with a
freshly prepared solution of Jones’ reagent (2.5  solution, 2.2 mL,
5.5 mmol) at 0 °C and the reaction mixture was stirred at room
temp. for 2 h. Excess reagent was decomposed by adding a few
drops of propan-2-ol and the reaction mixture was extracted with
diethyl ether. The extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent furnished the acid 11
(770 mg, 88%).[7] A solution of 11 (750 mg, 4.16 mmol) in MeOH
(4 mL) and a catalytic amount of concd. H2SO4 was refluxed for
6 h. The reaction mixture was then concentrated under vacuum and
extracted with diethyl ether (3 ϫ 5 mL). The combined diethyl
ether extract was washed with brine and dried (Na2SO4). Evapor-
ation of the solvent and purification of the residue over a silica-gel
column using ethyl acetate/hexane (1:20) as eluent furnished the
ester 11a (730 mg, 90%) as an oil. IR (neat): ν˜max. ϭ 3051, 1741,
1614, 1505, 1460, 1436, 1338, 1256, 1233, 1164, 1128, 1032, 808
cmϪ1 1H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 2.27 (s, 3 H,
.
ArCH3), 2.41 (t of d, J ϭ 14.0, 7.0 Hz, 1 H) and 2.73 (t of d, J ϭ
14.0, 7.0 Hz, 1 H, H-3), 3.64 (s, 3 H) and 3.80 (s, 3 H, 2 ϫ OCH3),
4.01 (t, J ϭ 7.5 Hz, 1 H, H-2), 4.94 (d, J ϭ 10 Hz, 1 H) and 5.02
(d, J ϭ 17 Hz, 1 H, H-5), 5.72 (t of dd, J ϭ 17.0, 10.0, 7.0 Hz, 1
H, H-4), 6.72 (d, J ϭ 8.1 Hz, 1 H, H-3Ј), 6.98 (d, J ϭ 8.1 Hz, 1
H, H-4Ј), 7.00 (s, 1 H, H-6Ј), ppm. 13C NMR (75 MHz, CDCl3 ϩ
CCl4): δ ϭ 20.7 (CH3), 36.8 (CH2), 43.9 (CH3), 51.7 (CH3), 55.6
(CH), 110.7 (CH), 116.5 (CH2), 127.2 (C), 128.5 (CH), 129.0 (CH),
129.8 (C), 136.0 (CH), 154.7 (C), 174.1 (C, OCϭO) ppm. MS:
m/z (%) ϭ 234 (29) [Mϩ], 193 (76), 175 (100), 165 (30), 163 (32),
149 (19), 135 (64), 105 (46), 91 (24). HRMS: m/z calcd. for
C14H18O3Na [M ϩ Na]: 257.1154, found 257.1172.
Methyl 2-Allyl-2-(2-methoxy-5-methylphenyl)pent-4-enoate (15): A
solution of nBuLi (2.5  in hexane, 2 mL, 5.0 mmol) was slowly
added to a cold (Ϫ78 °C), magnetically stirred solution of diisopro-
pylamine (0.8 mL, 5.56 mmol) in anhydrous THF (3 mL) and
stirred for 10 min. A solution of 14 (650 mg, 2.78 mmol) in anhy-
drous THF (2 mL) and HMPA (1 mL) were added dropwise to the
LDA thus formed and stirred for 40 min at the same temperature.
The enolate was treated with allyl bromide (0.47 mL, 5.56 mmol)
and stirred for 7 h. The reaction mixture was then diluted with
water and extracted with diethyl ether (3 ϫ 4 mL). The combined
diethyl ether extract was washed sequentially with 3  aqueous
HCl, saturated aqueous NaHCO3 solution and brine, and dried
(Na2SO4). Evaporation of the solvent and purification of the resi-
due over a silica-gel column using ethyl acetate/hexane (1:20) as
cmϪ1 1H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 2.27 (s, 3 H,
.
ArCH3), 3.55 (s, 2 H, H-2), 3.67 (s, 3 H) and 3.68 (s, 3 H, 2 ϫ
OCH3), 6.72 (d, J ϭ 8.1 Hz, 1 H, H-3Ј), 6.95 (s, 1 H, H-6Ј), 7.00
(d, J ϭ 8.1 Hz, 1 H, H-4Ј) ppm. 13C NMR (75 MHz, CDCl3
ϩ
CCl4): δ ϭ 20.6 (CH3), 35.6 (CH2), 51.7 (CH3), 55.5 (CH3), 110.4
(CH), 122.7 (C), 128.8 (CH), 129.5 (C), 131.7 (CH), 155.4 (C),
172.0 (C, OCϭO) ppm. MS: m/z (%) ϭ 194 (50) [Mϩ], 135 (100),
105 (80), 91 (35). HRMS: m/z calcd. for C11H14O3Na [M ϩ Na]:
217.0841, found 217.0841.
3-Methylbut-2-enyl (2-Methoxy-5-methylphenyl)acetate (8a): DCC
(206 mg, 1.00 mmol), DMAP (40 mg, 0.33 mmol) and 3-methylbut-
2-enol (0.07 mL, 0.67 mmol) were added to a magnetically stirred
solution of 11 (120 mg, 0.67 mmol) in anhydrous CH2Cl2 (4 mL) eluent furnished the ester 15 (655 mg, 86%) as an oil. IR (neat):
and stirred at room temp. for 6 h. The reaction mixture was then ν˜max. ϭ 3074, 1740, 1640, 1609, 1498, 1443, 1230, 1207, 1134, 1035,
1
concentrated under reduced pressure and filtered through a short
www.eurjoc.org
916, 809 cmϪ1. H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 2.31 (s,
Eur. J. Org. Chem. 2004, 499Ϫ503
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
501

A. Srikrishna, M. S. Rao
FULL PAPER
3 H, ArCH3), 2.60 (dd, J ϭ 13.8, 8.1 Hz, 2 H) and 2.76 (dd, J ϭ at room temp. Methyl iodide (0.07 mL, 1.15 mmol) was added to
13.8, 6.3 Hz, 2 H, 2 ϫ allylic CH2), 3.58 (s, 3 H) and 3.73 (s, 3 H, the reaction mixture, which was stirred at room temp. for 12 h. It
2 ϫ OCH3), 5.00 (d, 2 H, J ϭ 12 Hz), 5.01 (d, J ϭ 15.3 Hz, 2 H), was then quenched with water (5 mL) and extracted with diethyl
5.55Ϫ5.40 (m, 2 H), 6.72 (d, J ϭ 8.4 Hz, 1 H, H-3Ј), 6.92 (s, 1 H, ether (3 ϫ 3 mL). The combined diethyl ether extract was washed
H-6Ј), 7.00 (d, J ϭ 8.4 Hz, 1 H, H-4Ј) ppm. 13C NMR (75 MHz, with brine and dried (Na2SO4). Evaporation of the solvent and
CDCl3 ϩ CCl4): δ ϭ 21.1 (CH3), 38.0 (2 C, CH2), 50.6 (C, C-2), purification of the residue over a silica-gel column using ethyl acet-
51.4 (CH3), 55.3 (CH3), 111.0 (CH), 118.1 (2 C, CH2), 127.9 (CH), ate/hexane (1:10) as eluent furnished the keto ester 18 (39 mg, 71%)
128.3 (CH), 129.2 (C), 130.7 (C), 133.9 (2 C, CH), 154.6 (C), 175.6 as an oil. IR (neat): ν˜max. ϭ 1736, 1716, 1504, 1457, 1238, 1213,
(C, OCϭO) ppm. MS: m/z (%) ϭ 274 (20) [Mϩ], 233 (31), 201 (80), 1038 cmϪ1 1H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 0.63 (s, 3
.
173 (100), 158 (44), 145 (26), 128 (22), 115 (24), 105 (17). HRMS: H) and 1.39 (s, 3 H, 2 ϫ tert-CH3), 2.28 (s, 3 H, ArCH3), 3.61 (s,
m/z calcd. for C17H22O3Na [M ϩ Na]: 297.1467, found 297.1477.
For C17H23O3 [M ϩ 1]: 275.1647, found 275.1656.
3 H) and 3.72 (s, 3 H) [2 ϫ OCH3], 6.25 (d, J ϭ 6.0 Hz, 1 H, H-
4), 6.70 (d, J ϭ 7.5 Hz, 1 H, H-3Ј), 6.74 (s, 1 H, H-6Ј), 7.00 (d,
J ϭ 7.5 Hz, 1 H, H-4Ј), 7.50 (d, J ϭ 6.0 Hz, 1 H, H-5) ppm. 13C
NMR (75 MHz, CDCl3 ϩ CCl4): δ ϭ 21.0 (CH3), 21.3 (CH3), 26.4
(CH3), 52.1 (CH3), 52.7 (C, C-2), 55.0 (CH3), 66.4 (C, C-1), 111.2
(CH, C-3Ј), 127.1 (C, C-1Ј), 129.1 (CH), 129.5 (C, C-5Ј), 130.2
(CH), 132.1 (CH, C-4), 155.2 (C, C-2Ј), 158.1 (CH, C-5), 171.5 (C,
OCϭO), 210.6 (C, CϭO) ppm. MS: m/z ϭ 288 (19) [Mϩ], 229
(100), 214 (3), 145 (8), 115 (10). HRMS: m/z calcd. for C17H20O4Na
[M ϩ Na]: 311.1259, found 311.1248.
Methyl 1-(2-Methoxy-5-methylphenyl)cyclopent-3-ene-1-carboxy-
late (16): A solution of Grubbs’ catalyst (22 mg, 5 mol%) in anhy-
drous CH2Cl2 was added to a magnetically stirred solution of diene
15 (150 mg, 0.55 mmol) in anhydrous CH2Cl2 (5 mL) and stirred
at room temp. for 4 h. Evaporation of the solvent under reduced
pressure and purification of the residue on a silica-gel column using
ethyl acetate/hexane (1:10) as eluent furnished the cyclised com-
pound 16 (128 mg, 95%) as an oil. IR (neat): ν˜max. ϭ 3054, 1737,
1498, 1459, 1294, 1240, 1201, 1124, 1081, 1035, 809 cmϪ1
.
1H
Methyl 1-(2-Methoxy-5-methylphenyl)-2,2-dimethyl-3-oxocyclopen-
NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 2.30 (s, 3 H, ArCH3), 2.68 tane-1-carboxylate (19): A solution of enone 18 (30 mg, 0.10 mmol)
and 3.15 (2 ϫ d, J ϭ 15.6 Hz, 4 H, H-2 and H-5), 3.61 (s, 3 H) in ethanol (2 mL) was added to 5% PdϪC (5 mg). The reaction
and 3.75 (s, 3 H, 2 ϫ OCH3), 5.66 (s, 2 H, H-3 and H-4), 6.72 (d,
J ϭ 8.1 Hz, 1 H, H-3Ј), 6.93 (s, 1 H, H-6Ј), 6.98 (d, J ϭ 8.1 Hz, 1
mixture was stirred for 2 h at room temp. in an atmosphere of hy-
drogen, created by evacuative replacement of air (balloon) and then
H, H-4Ј) ppm. 13C NMR (75 MHz, CDCl3 ϩ CCl4): δ ϭ 21.0 the catalyst was filtered off. Evaporation of the solvent furnished
(CH3), 43.1 (2 C, CH2, C-2 and C-5), 52.0 (CH3, COOCH3), 54.0 the cyclopentanone 19 (27 mg, 90%) as an oil. IR (neat): ν˜max.
ϭ
1H
(C, C-1), 55.4 (CH3, ArOCH3), 110.9 (CH, C-3Ј), 126.9 (CH, C-
3030, 1743, 1726, 1499, 1465, 1250, 1120, 1028, 810 cmϪ1
.
4Ј), 128.0 (CH, C-6Ј), 128.3 (2 C, CH, C-3 and C-4), 129.2 (C, C- NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 0.80 (s, 3 H) and 1.16 (s, 3
1Ј), 133.0 (C, C-5Ј), 154.5 (C, C-2Ј), 177.1 (C, OCϭO) ppm. MS: H, 2 ϫ tert-CH3) 2.31 (s, 3 H, ArCH3), 2.65Ϫ2.30 (m, 4 H), 3.63
m/z (%) ϭ 246 (25) [Mϩ], 187 (82), 172 (28), 159 (12), 145 (43), 128 (s, 3 H) and 3.71 (s, 3 H, 2 ϫ OCH3), 6.76 (d, J ϭ 8.5 Hz, 1 H,
(25), 122 (100). HRMS: m/z calcd. for C15H18O3Na [M ϩ Na]:
269.1154, found 269.1153.
H-3Ј), 6.93 (s, 1 H, H-6Ј), 7.03 (d, J ϭ 8.5 Hz, 1 H, H-4Ј) ppm.
13C NMR (75 MHz, CDCl3 ϩ CCl4): δ ϭ 21.0 (CH3), 21.1 (CH3)
21.5 (CH3), 27.6 (CH2), 32.8 (CH2), 51.7 (CH3), 52.6 (C, C-2), 55.0
(CH3, OMe), 58.8 (C, C-1), 111.3 (CH, C-3Ј), 127.5 (C), 128.7
(CH), 128.8 (CH), 129.2 (C), 155.2 (C, C-2Ј), 174.8 (C, OCϭO),
217.7 (C, CϭO). MS: m/z (%) ϭ 290 (38) [Mϩ], 258 (25), 231 (100),
215 (23), 189 (42), 188 (75), 159 (30), 149 (39), 145 (42), 115 (30),
105 (32). HRMS: m/z calcd. for C17H22O4Na [M ϩ Na]: 313.1416,
found 313.1410.
Methyl 1-(2-Methoxy-5-methylphenyl)-3-oxocyclopent-4-ene-1-car-
boxylate (17): PDC (100 mg) was added to a solution of 16
(100 mg, 0.40 mmol) in pyridine (4 mL). The reaction mixture was
heated at 100 °C for 8 h, then cooled, filtered through a short silica-
gel column, and the column eluted with more CH2Cl2. Evaporation
of the solvent and purification of the residue over a silica-gel col-
umn using ethyl acetate/hexane (1:5) as eluent first furnished the
unchanged starting material (20 mg). Further elution of the column
with the same solvent furnished the enone 17 (55 mg, 65% based
on starting material consumed) as an oil. IR (neat): ν˜max. ϭ 3030,
Methyl
1-(2-Methoxy-5-methylphenyl)-2,2-dimethylcyclopentane-
carboxylate (21): A solution of 19 (5 mg, 0.017 mmol), ethanedi-
thiol (0.004 mL, 0.051 mmol) and BF3·Et2O (1 drop) in dry ben-
1739, 1720, 1614, 1500, 1463, 1430, 1246, 1194, 1150, 1135, 1034, zene (1 mL) was magnetically stirred at 0 °C to room temp. for 4 h.
1
815 cmϪ1. H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 2.28 (s, 3 H, The reaction was then quenched with aqueous NaHCO3 solution
ArCH3), 2.26 and 3.56 (2 ϫ d, J ϭ 18.3 Hz, 2 H, H-2), 3.67 (s, 3 and extracted with diethyl ether. The diethyl ether extract was
H) and 3.78 (s, 3 H, 2 ϫ OCH3), 6.34 (d, J ϭ 6.0 Hz, 1 H, H-4),
washed with 5% aqueous NaOH solution and brine and dried
6.75 (d, J ϭ 8.1 Hz, 1 H, H-3Ј), 6.78 (s, 1 H, H-6Ј), 7.04 (d, J ϭ (Na2SO4). Evaporation of the solvent and purification of the resi-
8.1 Hz, 1 H, H-4Ј), 7.75 (d, J ϭ 6.0 Hz, 1 H, H-5) ppm. 13C NMR
(75 MHz, CDCl3 ϩ CCl4): δ ϭ 20.8 (CH3, ArCH3), 46.0 (CH2, C-
due over a silica-gel column using ethyl acetate/hexane (1:20) as
eluent furnished the thioketal 20 (5 mg, 83%) as an oil. IR (neat):
2), 52.8 (CH3) and 55.5 (CH3, 2 ϫ OMe), 57.6 (C, C-1), 111.0 (CH, ν˜max. ϭ 1739, 1498, 1464, 1248, 1193, 1131, 1034, 808 cmϪ1 1H
.
C-3Ј), 127.3 (CH, C-6Ј), 129.2 (CH, C-4Ј), 130.0 (C), 130.7 (C), NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 0.65 (s, 3 H) and 1.57 (s, 3
135.3 (CH, C-4), 154.4 (C, C-2Ј), 161.9 (CH, C-5), 172.6 (C, OCϭ H, 2 ϫ tert-CH3), 2.30 (s, 3 H, ArCH3), 2.80Ϫ2.05 (m, 4 H),
O), 206.8 (CϭO) ppm. MS: m/z (%) ϭ 260 (29) [Mϩ], 201 (100), 3.35Ϫ3.00 (m, 4 H), 3.53 (s, 3 H) and 3.71 (s, 3 H, 2 ϫ OCH3),
186 (46), 158 (11), 128 (19), 115 (17). HRMS: m/z calcd. for
C15H16O4Na [M ϩ Na]: 283.0946, found 283.0943. For C15H17O4
[M ϩ 1]: 261.1126, found 261.1129.
6.66 (d, J ϭ 8.4 Hz, 1 H, H-3Ј), 6.95 (d, J ϭ 8.4 Hz, 1 H, H-4Ј),
7.00 (s, 1 H, H-6Ј) ppm. 13C NMR (100 MHz, CDCl3 ϩ CCl4):
δ ϭ 21.0, 23.0, 30.4, 35.6, 38.0, 38.7, 45.1, 51.3, 52.1, 54.9, 59.1,
82.8 (SϪCϪS), 110.4, 128.0, 128.5, 128.8, 131.5, 155.3, 175.4
(OCϭO) ppm. MS: m/z (%) ϭ 366 (5) [Mϩ], 335 (5), 206 (18), 189
(5), 173 (5), 159 (5), 145 (8), 131 (100), 115 (5), 105 (6).
Methyl 1-(2-Methoxy-5-methylphenyl)-2,2-dimethyl-3-oxocyclopent-
4-ene-1-carboxylate (18): A solution of keto ester 17 (50 mg,
0.19 mmol) in DME (2 mL) was added to a magnetically stirred
suspension of NaH (46 mg, 60% dispersion in oil, 1.15 mmol,
washed with dry hexanes) in DME (2 mL) and stirred for 40 min
An excess of Raney nickel was added to a magnetically stirred solu-
tion of 20 (4 mg, 0.01 mmol) in dry ethanol (1 mL) and refluxed
502
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 499Ϫ503

A Formal Total Synthesis of ( )-1,13-Herbertenediol
FULL PAPER
for 3 h. The reaction mixture was cooled and filtered through a
short silica-gel column to remove the catalyst. Evaporation of the
solvent and purification of the residue over a silica-gel column
using ethyl acetate/hexane (1:50) as eluent furnished the ester 21
(2.5 mg, 85%) as an oil. IR (neat): ν˜max. ϭ 1738, 1248, 1195, 807
cmϪ1. 1H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 0.69 (s, 3 H) and
1.25 (s, 3 H, 2 ϫ tert-CH3), 1.65Ϫ1.50 (m, 1 H), 1.85Ϫ1.70 (m, 2
H), 2.25Ϫ1.95 (m, 2 H), 2.31 (s, 3 H, ArCH3), 2.60Ϫ2.48 (1 H, t
of d, J ϭ 13.5, 6.0 Hz), 3.54 (s, 3 H) and 3.70 (s, 3 H, 2 ϫ OCH3),
6.69 (d, J ϭ 8.1 Hz, 1 H, H-3Ј), 6.97 (d, J ϭ 8.1 Hz, 1 H, H-4Ј),
7.05 (s, 1 H, H-6Ј) ppm. 13C NMR (75 MHz, CDCl3 ϩ CCl4): δ ϭ
20.1 (CH2, C-4), 21.2 (CH3), 25.1 (CH3), 27.7 (CH3), 34.8 (CH2),
39.9 (CH2), 45.5 (C, C-2), 51.0 (CH3), 54.9 (CH3), 60.3 (C, C-1),
110.7 (CH, C-3Ј), 127.9 (CH, C-6Ј), 128.6 (C, C-1Ј), 128.9 (CH, C-
4Ј), 129.9 (C, C-5Ј), 155.4 (C, C-2Ј), 175.5 (C, OCϭO) ppm. MS:
m/z (%) ϭ 276 (18) [Mϩ], 217 (11), 207 (21), 194 (36), 175 (100),
162 (23), 149 (84), 147 (74), 135 (40), 119 (22), 105 (27), 91 (35).
HRMS: m/z calcd. for C17H24O3Na [M ϩ Na]: 299.1623, found
299.1630.
HRMS: m/z calcd. for C15H18O2Na [M ϩ Na]: 253.1204, found
253.1218.
Acknowledgments
We thank Professor Y. Asakawa for providing the copy of the H
1
NMR spectrum of the diol 3, Mr. G. Satyanarayana for carrying
out the last experiment and the C.S.I.R., New Delhi for financial
support.
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dropwise to a solution of 21 (13 mg, 0.047 mmol) in CH2Cl2 (1 mL)
at Ϫ40 °C and the reaction mixture was stirred for 3 h at room
temp. It was then quenched with saturated aqueous NaHCO3 solu-
tion and extracted with CH2Cl2 (3 ϫ 2 mL). The combined organic
layer was washed with brine and dried (Na2SO4). Evaporation of
the solvent and purification of the residue over a silica-gel column
using ethyl acetate/hexane (1:10) as eluent furnished the lactone 22
(7 mg, 65%) as an oil. IR (neat): ν˜max. ϭ 1798, 1643, 1617, 1038
cmϪ1. 1H NMR (300 MHz, CDCl3 ϩ CCl4): δ ϭ 0.92 (s, 3 H) and
1.03 (s, 3 H, 2 ϫ tert-CH3), 2.40Ϫ1.64 (m, 6 H), 2.36 (s, 3 H,
ArCH3), 6.94 (d, J ϭ 8.4 Hz, 1 H, H-7), 6.96 (s, 1 H, H-4), 7.04
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(d, J ϭ 8.4 Hz, 1 H, H-6) ppm. 13C NMR (75 MHz, CDCl3
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[6c]
36, 2037Ϫ2055.
39, 3013Ϫ3043.
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CCl4): δ ϭ 21.0 (CH2, C-4Ј), 21.5 (CH3), 23.6 (CH3), 25.4 (CH3),
34.7 (CH2), 38.7 (CH2), 47.6 (C, C-2Ј), 60.1 (C, C-3), 110.1 (CH,
C-7), 125.6 (CH, C-4), 128.9 (CH, C-6), 129.3 (C, C-3a), 132.5 (C,
C-5), 151.7 (C, C-7a), 179.4 (C, C-2) ppm. MS: m/z (%) ϭ 230 (11)
[Mϩ], 161 (100), 160 (81), 148 (16), 135 (37), 115 (11), 91 (15).
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Received September 19, 2003
Eur. J. Org. Chem. 2004, 499Ϫ503
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
503