Synthesis of (+)-trixagol and its enantiomer, the terpenoid side chain of (-)-agelasine E

Article abstract of DOI:10.1016/S0040-4020(02)01455-2

The naturally occurring γ-cyclogeranylgeraniol called (+)-trixagol has been synthesised for the first time. Trixagol was readily available in five steps from (S)-2,2-dimethyl-6-methylene-1-cyclohexanemethanol. The enantiomer of trixagol, which equates to

Full text of DOI:10.1016/S0040-4020(02)01455-2

Tetrahedron 59 (2003) 115–121
Synthesis of (1)-trixagol and its enantiomer, the terpenoid side
chain of (2)-agelasine E
*
Anne Kristin Bakkestuen and Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, Blindern P.O. Box 1033, N-0315 Oslo, Norway
Received 30 August 2002; revised 10 October 2002; accepted 7 November 2002
Abstract—The naturally occurring g-cyclogeranylgeraniol called (þ)-trixagol has been synthesised for the first time. Trixagol was readily
available in five steps from (S)-2,2-dimethyl-6-methylene-1-cyclohexanemethanol. The enantiomer of trixagol, which equates to the
terpenoid side chain of the naturally occurring 7,9-dialkylpurinium salt (2)-agelasine E, was prepared from the (R) enantiomer of the
cyclohexanemethanol. Both trixagol enantiomers were moderately active against Mycobacterium tuberculosis. q 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
of naturally occurring bioactive purinium salts,14 as well
as antimycobacterial purines,15–17 we are now working
towards the synthesis of agelasine E. We herein report
the first synthesis of (þ)-trixagol and its enantiomer, the
terpenoid part of (2)-agelasine E.
In 1975, 7,9-dialkylpurinium salts were isolated from the
marine sponge Agelas dispar,1 and at the present a total of
11 9-methyladeninium salts, agelasine A-I, epiagelasine C
and agelin B, has been isolated from Agelas species.2–8 All
of these compounds carry a diterpenoid side chain in the
adenine 7-position. At the present time, only (2)-agelasine
A,9 (2)-agelasine B,10 and (^)-agelasine F,11 have been
synthesised. The Agelasines are associated with bio-
activities like antimicrobial and cytotoxic effects as well
as contractive responses of smooth muscles and inhibition
of Na, K-ATPase. Furthermore in vitro activity against
Mycobacterium tuberculosis has recently been reported
for agelasine F.12 The terpenoid side chain of agelasine E
(Fig. 1) is the enantiomer of the g-cyclogeranylgeraniol,
called trixagol, found in the plant Bellardia trixago (L).13 In
connection with our projects directed towards the synthesis
2. Results and discussion
As a model substance for trixagol, we first chose to prepare
the geraniol derivative 5 (Scheme 1). Geraniol was
converted to the allylic alcohol 1 essentially as described
before,18 and the alcohol was reacted with diphenyldisulfide
in the presence of tributylphosphine to give the sulfide 2 in
high yield. Deprotonation of compound 2 with n-BuLi and
DABCO, and subsequent reaction with bromomethylcyclo-
hexane gave the cyclohexyl derivative 3 and the phenylthio
group was easily removed with Raney-Nickel or sodium in
tert-butanol, but compound 4 was formed as an essentially
1:1 E/Z-mixture. In order to avoid this isomerisation,
we decided to move the sulfur substituent away from the
allylic position.19 The allylic alcohol 1 was converted to the
tosylate 6. Reaction between the alcohol 1 and tosyl
chloride (TsCl) in pyridine was slow and the chloride was
formed rather than the desired product. When the reaction
was performed in the presence of trimethylammonium
chloride and triethylamine,20 however, the tosylate 6 was
formed essentially quantitatively. Cyclohexylmethane-
sulfonylbenzene 9, prepared from cyclohexylmethanol 7
and diphenyldisulfide followed by oxone (89% yield) or
m-CPBA (80% yield) oxidation of the sulfide 8, was
deprotonated with n-BuLi in the presence of DMPU and
reacted with the tosylate 6 to give compound 10. The
sulfonyl group was removed with sodium-amalgam in
methanol to give compound 4 as the pure E,E isomer, and
finally the THP-protecting group was removed under mild
Figure 1.
Keywords: alkylation; antibacterials; natural products; sulfones; terpenoids.
*
Corresponding author. Tel.: þ47-22-857-019; fax: þ47-22-855-507;
e-mail: l.l.gundersen@kjemi.uio.no
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01455-2

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A. K. Bakkestuen, L.-L. Gundersen / Tetrahedron 59 (2003) 115–121
Scheme 1. Reagents and conditions: (i) PhSSPh, Bu3P, pyridine; (ii) n-BuLi, DABCO, bromomethylcyclohexane, THF, 08C; (iii) Raney-Ni, EtOH, 08C;
(iv) PPTS, EtOH, 558C; (v) TsCl, Me3NHCl, Et3N, toluene; (vi) oxone, MeOH, H2O, 08C to rt; (vii) n-BuLi, DMPU, THF, 08C; (viii) NaHg, Na2HPO4, MeOH.
conditions employing pyridinium p-toluenesulfonate
(PPTS).21
reported m-CPBA oxidation of (^)-12,26 we were only able
to isolate the desired product in 33 % yield due to concurrent
epoxidation of the exocyclic double bond. The sulfones 13
were coupled with the geraniol part as described for the
synthesis of compound 4 above. In the sodium mediated
reduction of the sulfones 14 to compounds 15, Na2HPO4
was included in order to minimise unwanted elimination.27
The desired compounds 15 could be separated from small
amounts of elimination products on silica gel impregnated
with silver nitrate. Reductions with metallic sodium gave
better results than with sodium-amalgam and attempts
to remove the sulfonyl group with lithium metal and
ethylamine28 met with little success. After PPTS mediated
protecting group cleavage, we isolated (þ)-trixagol 16a or
its enantiomer 16b in high yields. We found the optical
rotations of the synthetic trixagol enantiomers to be
numerically considerably higher than what has been
reported for naturally occurring trixagol. This might
indicate that natural trixagol is formed largely through
non-enzymic processes. Both enantiomers of trixagol 16
were tested as potential antimycobacterials; at 6.25 mg/mL
the inhibition of M. tuberculosis was 36% for (þ)-trixagol
16a and 61% for the agelasine E side chain 16b. In the same
assay, the alcohol 5 exhibited 49% inhibition.
The enantiomeric sulfones 13a and 13b required for the
introduction of the cyclohexyl part of (þ)-trixagol and
(2)-agelasine E, were prepared from the alcohols 11
(Scheme 2). Both enantiomers of compound 11 are
available from 4-methylpent-3-en-2-one and dimethyl
malonate by literature methods.22–24 The alcohols 11
were converted to the sulfides 12 in one step and compounds
12 were oxidised selectively to the corresponding sulfones
13 by applying oxone.25 When we attempted the previously
3. Experimental
3.1. General
1
The H NMR spectra were recorded at 500 MHz with a
Bruker Avance DRX 500 Mz instrument, and the 1H
decoupled 13C NMR spectra were recorded at 50 MHz
using a Bruker Avance DPX 200 Mz instrument. Assign-
1
ments of H and 13C resonances are based on APT, DEPT
and / or on 2D NMR experiments (COSY, HMBC, HMQC
NOESY). Mass spectra under electron impact conditions
(EI) were recorded at 70 eV ionising voltage with a VG
Prospec instrument, and are presented as m/z (% rel. int.).
CH4 was employed as the ionisation gas for chemical
ionisation (CI). IR spectra were recorded on a Nicolet
Scheme 2. Reagents and conditions: (i) PhSSPh, Bu3P, pyridine; (ii) oxone,
MeOH, H2O, 08C to rt; (iii) n-BuLi, DMPU, comp. 6, THF, 08C to rt;
(iv) Na, Na2HPO4, EtOH, THF; (v); (vi) PPTS, EtOH, 558C.

A. K. Bakkestuen, L.-L. Gundersen / Tetrahedron 59 (2003) 115–121
117
Magna 550 instrument. Elemental analyses were performed
by Ilse Beetz Mikroanalytisches Laboratorium, Kronach,
Germany. Melting points are uncorrected. Silica gel for
flash chromatography was purchased from Merck,
Darmstadt, Germany (Merck No. 9385). Analytical thin
layer chromatography was performed with E. Merck silica
gel 60F254 0.25 mm plates (Merck No. 1.05554). THF was
distilled from sodium-benzophenone. DMF was distilled
reach ambient temperature before diethyl ether (50 mL) was
added and the mixture was washed with water (2£25 mL)
and brine (25 mL), dried (MgSO4) and evaporated in vacuo.
The product was purified by flash chromatography eluting
with EtOAc–hexane (1:15); yield 113 mg (51%), colourless
liquid; dH (500 MHz, CDCl3) 0.82–0.96 (3H, m), 1.09–
1.36 (5H, m), 1.49–1.75 (10H, m), 1.607 (3H, br s, CH3),
1.614 (3H, br s, CH3), 1.80–1.85 (3H, m), 1.98–2.02 (2H,
dd, J¼15.0, 7.6 Hz, H-5), 3.49–3.53 (1H, m, THP), 3.70–
3.74 (1H, dd, J¼8.9, 6.8 Hz, H-8), 3.86–3.91 (1H, m, THP),
3.98 (1H, dd, J¼11.8, 7.3 Hz, CHaHbOTHP), 4.21 (1H, dd,
J¼11.8, 6.4 Hz, CHaHbOTHP), 4.60–4.62 (1H, m, H-2 in
THP), 4.98 (1H, t, J¼7.0 Hz, H-6), 5.27 (1H, dd, J¼7.3,
6.4 Hz, H-2), 7.17–7.28 (3H, m, Ph), 7.30–7.33 (2H, m,
Ph); dC (50 MHz, CDCl3) 11.5 (CH3), 16.3 (CH3), 19.6
(CH2 in THP), 25.5 (CH2), 26.0 (CH2), 26.1 (CH2), 26.2
(CH2), 26.5 (CH2), 30.7 (CH2), 32.7 (CH2), 33.6 (CH2), 35.3
(C-10), 39.0 (C-4), 40.0 (CH2), 56.1 (C-8), 62.2 (C-6 in
THP), 63.6 (C-1), 97.8 (C-2 in THP), 120.6 (C-2), 126.7
(CH in Ph), 127.9 (C-6), 128.4 (CH in Ph), 132.8 (CH in
Ph), 133.5 (C-7), 135.7 (C in Ph), 139.8 (C-3); m/z (CI, CH4)
443 (3, MHþ), 442 (5, Mþ), 342 (25), 341 (100), 273 (11),
249 (11), 232 (14), 231 (75), 163 (10), 135 (14), 85 (72), 61
(13).
˚
from BaO and DMPU from CaH2 and stored over 4 A
molsieve. Pyridine in Sure/Seale bottles was purchased
from Aldrich, Buchs, Switzerland. (2E,6E)-3,7-Dimethyl-1-
(tetrahydro-2-pyranyloxy)-2,6-octadien-8-ol,18 and (S) and
(R)-(þ)-2,2-dimethyl-6-methylene-1-cyclohexanemethanol
(%ee$98; GC)22 – 24 were prepared according to
literature procedures. All other reagents were com-
mercially available and used as received. Screening of
antimycobacterial activity was performed as previously
reported.17
3.1.1. (2E,6E)-3,7-Dimethyl-8-phenylthio-1-(tetrahydro-
2-pyranyloxy)-2,6-octadiene 2. A mixture of (2E,6E)-3,7-
dimethyl-1-(tetrahydro-2-pyranyloxy)-2,6-octadien-8-ol
1
(538 mg, 2.11 mmol) and diphenyldisulfide (1.393 g,
6.19 mmol) in dry pyridine (1 mL) was stirred at ambient
temperature under N2-atm. for 30 min. Tributylphosphine
(1.6 mL, 6.16 mmol) was added and the resulting mixture
was stirred for an additional 2.5 h, before EtOAc (100 mL)
and water (25 mL) were added. The phases were separated
and the organic layer was washed with 10% HCl(aq)
(25 mL), 10% NaOH(aq) (25 mL) and brine (25 mL), dried
(MgSO4) and evaporated in vacuo. The product was purified
by flash chromatography eluting with EtOAc–hexane
(1:15); yield 657 mg (90%), colourless liquid [Found: C,
73.00; H, 8.60. C21H30O2S requires C, 72.80; H, 8.73%];
3.1.3. (2E,6E)-9-Cyclohexyl-3,7-dimethyl-1-(tetrahydro-
2-pyranyloxy)-2,6-nonadiene 4. Method A: A solution of
(2E,6E)-9-cyclohexyl-3,7-dimethyl-8-phenylthio-1-(tetra-
hydro-2-pyranyloxy)-2,6-nonadiene 3 (261 mg, 0.59 mmol)
in abs. EtOH (15 mL) was added dropwise to a stirred
mixture of Raney-Nickel (3.551 g of a 50% suspension in
water) in abs. EtOH (20 mL) at 08C. The reaction
mixture was stirred at 08C for 40 min and filtered through
celite. The celite was washed with EtOH (50 mL) and
the combined EtOH solutions were evaporated in vacuo.
The product was purified by flash chromatography eluting
with EtOAc–hexane (1:15); yield 150 mg (76%) as a ca. 1:1
mixture of the 6E,6E and 6Z,2E isomers; colourless
liquid.
n
max(liquid film): 3056, 2939–2849 (br) cm21 dH
(500 MHz, CDCl3) 1.50–1.62 (5H, m, THP), 1.64 (3H, br
s, CH3), 1.66–1.75 (1H, m, THP), 1.73 (3H, br s, CH3), 1.95
(2H, m, H-4), 2.09 (2H, m, H-5), 3.48 (2H, br s, H-8), 3.52
(1H, m, H-6a in THP), 3.89 (1H, m, H-6b in THP), 4.00 (1H,
dd, J¼12.0, 7.3 Hz, CHaHbOTHP), 4.22 (1H, dd, J¼12.0,
6.5 Hz, CHaHbOTHP), 4.62 (1H, dd, J¼4.6, 3.1 Hz, H-2 in
THP), 5.21 (1H, t, J¼7.0 Hz, H-6), 5.31 (1H, dd, J¼7.3,
6.5 Hz, H-2), 7.17 (1H, m, Ph), 7.2–7.3 (2H, m, Ph), 7.32
(2H, m, Ph); dC (50 MHz, CDCl3) 15.2 (CH3), 16.3 (CH3),
19.6 (CH2 in THP), 25.5 (CH2 in THP), 26.3 (C-5), 30.7
(CH2 in THP), 39.1 (C-4), 44.2 (C-8), 62.3 (C-6 in THP),
63.6 (C-1), 97.9 (C-2 in THP), 120.8 (C-2), 126.2 (CH in
Ph), 128.4 (CH in Ph), 128.6 (C-6), 130.5 (CH in Ph), 136.5
(C-7), 139.7 (C-3), 1 signal was hidden; m/z (EI) 346 (2,
Mþ), 177 (20), 176 (18), 135 (20), 110 (15), 109 (16), 93
(14), 85 (100), 84 (17), 67 (20).
Method B. To a mixture of (2E,6E)-9-benzenesulfonyl-9-
cyclohexyl-3,7-dimethyl-1-(tetrahydro-2-pyranyloxy)-2,6-
nonadiene 10 (405 mg, cont. ca. 25% of comp. 9) and
Na2HPO4 (545 mg, 3.8 mmol) in methanol (10 mL) was
added NaHg 5% (2.508 g, 5.5 mmol Na) and the resulting
mixture was stirred at ambient temperature for 2 h. Water
(25 mL) and diethyl ether (50 mL) was added, the mixture
was decanted and the phases separated. The ethereal layer
was washed with sat. NH4Cl(aq) (25 mL) and brine
(25 mL), dried (MgSO4) and evaporated in vacuo. The
product was purified by flash chromatography eluting with
EtOAc–hexane (1:15); yield 192 mg (50%) in two steps
from comp. 9, colourless liquid [Found: C, 79.00; H, 11.54.
C22H38O2 requires C, 78.99; H, 11.45%]; dH (500 MHz,
CDCl3) 0.80–0.88 (1H, m), 1.01–1.25 (6H, m), 1.49–1.74
(11H, m), 1.55 (3H, br s, CH3), 1.65 (3H, br s, CH3), 1.78–
1.85 (1H, m), 1.91–1.95 (2H, m, H-8), 2.00–2.05 (2H, m,
H-4), 2.05–2.11 (2H, m, H-5), 3.47–3.51 (1H, m, H-6a in
THP), 3.85–3.89 (1H, m, H-6b in THP), 4.01 (1H, dd, J¼
12.0, 7.6 Hz, CHaHbOTHP), 4.21 (1H, dd, J¼12.0, 6.3 Hz,
CHaHbOTHP), 4.59–4.61 (1H, m, H-2 in THP), 5.07 (1H, t,
J¼7.0 Hz, H-6), 5.34 (1H, dd, J¼7.6, 6.3 Hz, H-2); dC
(50 MHz, CDCl3) 16.0 (CH3), 16.4 (CH3), 19.6 (CH2), 25.4
3.1.2. (2E,6E)-9-Cyclohexyl-3,7-dimethyl-8-phenylthio-
1-(tetrahydro-2-pyranyloxy)-2,6-nonadiene 3. A mixture
of (2E,6E)-3,7-dimethyl-8-phenylthio-1-(tetrahydro-2-pyr-
anyloxy)-2,6-octadiene
2
(173 mg, 0.50 mmol) and
DABCO (224 mg, 2.0 mmol) in dry THF (5 mL) was
stirred at ambient temperature under N2-atm. for 30 min and
cooled to 08C, before n-BuLi (1.25 mL of a 1.6 M solution
in hexane, 2.0 mmol) was added dropwise. After 30 min
at 08C, a solution of bromomethylcyclohexane (90 mg,
0.51 mmol) in dry THF (3 mL) was added dropwise. The
resulting mixture was stirred at 08C for 3 h and allowed to

118
A. K. Bakkestuen, L.-L. Gundersen / Tetrahedron 59 (2003) 115–121
(C-5), 26.3 (CH2), 26.4 (CH2), 26.7 (CH2), 30.7 (CH2), 33.3
(CH2), 35.8 (C-9), 37.0 (C-8), 37.4 (C-10), 39.6 (CH2), 62.2
(C-6 in THP), 63.6 (C-1), 97.7 (C-2 in THP), 120.6 (C-2),
123.4 (C-6), 135.9 (C-7), 140.2 (C-3); m/z (CI, CH4) 335
(0.1, MHþ), 233 (28), 232 (10), 137 (10), 121 (8), 109 (20),
95 (19), 85 (100).
was stirred for 13 h, diluted with ethyl acetate (100 mL),
washed with 10% HCl(aq) (25 mL), 10% NaOH(aq)
(25 mL) and brine (25 mL), dried (MgSO4) and evaporated
in vacuo. The product was purified by flash chromatography
eluting with acetone–hexane (1:100); yield 2.303 g (95%),
colourless liquid; Spectral data were in good agreement with
those reported before.29
3.1.4. (2E,6E)-9-Cyclohexyl-3,7-dimethyl-2,6-nonadien-
1-ol 5. A mixture of (2E,6E)-9-cyclohexyl-3,7-dimethyl-
3.1.7. Cyclohexylmethyl)sulfonylbenzene 9. A solution of
oxone (8.260 g, 13.4 mmol) in water (35 mL) was added
to a stirred solution of (cyclohexylmethyl)thiobenzene 8
(1.848 g, 8.95 mmol) in methanol (35 mL) at 08C. When the
addition was complete, the cooling bath was removed and
the reaction mixture was stirred for 19 h at ambient
temperature before diethyl ether (200 mL) was added and
the resulting mixture was washed with water (100 mL) and
brine (50 mL), dried (MgSO4) and evaporated in vacuo. The
product was purified by flash chromatography eluting with
acetone–hexane (1:5); yield 1.896 g (89%), colourless
liquid which solidified upon standing, mp 56–578C (lit.30
53–548C).
1-(tetrahydro-2-pyranyloxy)-2,6-nonadiene
4
(56 mg,
0.17 mmol) and pyridinium p-toluenesulfonate (11 mg,
0.04 mmol) in ethanol (2 mL) was stirred at 558C under
N2-atm. for 13 h, before the mixture was evaporated in
vacuo and the residue was purified by flash chromatography
eluting with acetone–hexane (1:5); yield 39 mg (93%), pale
yellow oil [Found C, 81.28; H, 11.66. C17H30O requires C,
81.54; H, 12.08]; dH (500 MHz, CDCl3) 0.80–0.88 (2H, m),
1.00–1.25 (5H, m, H-9 and cyclohexyl), 1.29 (1H, br s,
OH), 1.56 (3H, br s, CH3), 1.65 (3H, br s, CH3), 1.59–1.69
(6H, m, cyclohexyl), 1.92–1.95 (2H, m, H-8), 1.99–2.02
(2H, m, H-4), 2.06–2.10 (2H, m, H-5), 4.12 (2H, d, J¼
6.9 Hz, H-1), 5.07 (1H, t, J¼6.9 Hz, H-6), 5.39 (1H, t,
J¼6.9 Hz, H-2); dC (50 MHz, CDCl3) 15.9 (CH3), 16.2
(CH3), 26.3 (C-5), 26.4 (CH2), 26.7 (CH2), 33.3 (CH2), 35.8
(C-9), 37.0 (C-8), 37.3 (C-10), 39.5 (C-4), 59.3 (C-1),
123.25 (C-6), 123.30 (C-2), 136.1 (C-7), 139.8 (C-3); m/z
(EI): 250 (7, Mþ), 123 (24), 109 (87), 95 (94), 93 (46), 83
(78), 81 (54), 69 (46), 67 (40), 55 (100).
3.1.8. (2E,6E)-9-Benzenesulfonyl-9-cyclohexyl-3,7-di-
methyl-1-(tetrahydro-2-pyranyloxy)-2,6-nonadiene 10.
n-Butyllithium (2.5 mL, 1.4 M sol., 3.5 mmol) was added
dropwise to a stirred solution of cyclohexylmethanesulfo-
nylbenzene 9 (414 mg, 1.74 mmol) in THF (10 mL) at 08C
under N2-atm. and the resulting mixture was stirred at 08C
for 30 min before a solution of crude (2E,6E)-3,7-dimethyl-
1-(tetrahydro-2-pyranyloxy)-2,6-octadien-8-yl 4-methyl-
benzenesulfonate 6 (710 mg, ca. 1.74 mmol) and DMPU
(2.5 mL, 21 mmol) in THF (3 mL) was added. The reaction
mixture was stirred for 20 h while reaching ambient
temperature. Diethyl ether (50 mL) was added and the
mixture was washed with sat. NH4Cl(aq) (25 mL), water
(3£25 mL) and brine (25 mL), dried (MgSO4) and evapo-
rated in vacuo. The product was partly purified by flash
chromatography eluting with acetone–hexane (1:5); yield
608 mg (diastereomeric mixture of the compounds 10 cont.
ca 25% starting material 9), colourless oil. Further purifi-
cation gave an analytical sample [Found: C, 70.77 H, 8.79.
C28H42O4S requires C, 70.85; H, 8.92%]. Spectral data for
the diastereomeric mixture: dH (500 MHz, CDCl3) 1.00–
1.10 (1H, m), 1.14–1.25 (2H, m), 1.26 (3H, br s, CH3),
1.31–1.41 (2H, m), 1.43–1.58 (6H, m), 1.62 (3H, br s,
CH3), 1.57–1.65 (1H, m), 1.66–1.75 (2H, m), 1.77–1.86
(2H, m), 1.89–1.98 (4H, m, H-4 and H-5), 2.14–2.21 (1H,
m), 2.36–2.46 (2H, m, H-8), 3.01–3.04 (1H, t, J¼6.8 Hz,
H-9), 3.46–3.50 (1H, m, H-6a in THP), 3.83–3.88 (1H, m,
H-6b in THP), 3.97 (1H, dd, J¼11.8, 7.4 Hz, CHaHbOTHP),
4.20 (1H, dd, J¼11.8, 6.4 Hz, CHaHbOTHP), 4.58 (1H, m,
H-2 in THP), 5.12 (1H, br s, H-6), 5.30 (1H, dd, J¼7.4,
6.4 Hz, H-2), 7.48–7.51 (2H, m, Ph), 7.57–7.60 (3H, m,
Ph); dC (50 MHz, CDCl3) 15.0 (CH3), 16.35 and 16.37
(CH3), 19.61 and 19.60 (CH2 in THP), 25.4 (CH2 in THP),
26.1 (CH2), 26.2 (C-5), 26.4 (CH2), 27.1 (CH2), 28.3 (CH2),
30.7 (CH2), 31.3 (CH2), 35.3 (CH2), 37.4 (C-10), 39.0 (C-4),
62.28 and 62.29 (C-6 in THP), 63.61 and 63.62 (C-1), 66.7
(C-9), 97.90 and 97.92 (C-2 in THP), 120.8 (C-2), 128.2
(C-6), 128.5 (CH in Ph), 128.9 (CH in Ph), 130.2 (C-7),
133.2 (CH in Ph), 139.6 (C in Ph), 139.8 (C-3); m/z (EI) 474
(0.3 Mþ), 389 (28), 231 (47), 230 (51), 229 (28), 163 (39),
135 (23), 121 (22), 93 (18), 85 (100).
3.1.5. (2E,6E)-3,7-Dimethyl-1-(tetrahydro-2-pyranyl-
oxy)-2,6-octadien-8-yl 4-methylbenzenesulfonate 6. A
solution of tosyl chloride (314 mg, 1.6 mmol) in toluene
(3 mL), was added to a stirred solution of (2E,6E)-3,7-
dimethyl-1-(tetrahydro-2-pyranyloxy)-2,6-octadien-8-ol
1
(382 mg, 1.5 mmol), trimethylammonium hydrochloride
(142 mg, 1.5 mmol) and triethylamine (0.52 mL,
3.7 mmol) in toluene (3 mL) under N2-atm. The resulting
mixture was stirred for 2 h, diluted with diethyl ether
(100 mL), washed with water (2£25 mL) and brine
(25 mL), dried (MgSO4) and evaporated in vacuo; yield
572 mg, pale yellow oil which was used directly without
further purification; dH (500 MHz, CDCl3, 08C) 1.50–1.61
(4H, m), 1.58 (3H, s, –C4H6–CH3), 1.66 (3H, br s, CH3),
1.71–1.76 (1H, m), 1.80–1.85 (1H, m), 1.99–2.02 (2H, m,
H-4), 2.08–2.13 (2H, m, H-5), 2.46 (3H, br s, CH3), 3.50–
3.53 (1H, m), 3.87–3.92 (1H, m,), 4.00 (1H, dq, J¼11.7,
7.5 Hz), 4.25 (1H, dq, J¼11.7, 6.5 Hz), 4.40 (2H, br s, H-8),
4.61–4.63 (1H, m), 5.32–5.35 (1H, H-2), 5.40–5.43 (1H,
m, H-6), 7.36 (2H, d, J¼8.1 Hz, Ar), 7.84 (2H, d, J¼8.1 Hz,
Ar); dC (50 MHz, CDCl3) 13.6 (–C4H6–CH3), 16.3 (CH3),
19.5 (CH2); 21.7 (CH3), 25.3 (CH2), 25.8 (C-5), 30.5 (CH2),
38.4 (CH2), 62.3 (CH2O–THP), 63.5 (C-1), 76.8 (CH2OTs),
97.9 (CHO–THP), 120.7 (C-2), 127.8 (CH in Ph), 128.3 (C
in Ph); 129.7 (CH in Ph), 132.3 (C-6), 133.0 (C in Ph), 139.4
(C-3), 144.6 (C-7); m/z (CI, CH4): 335 (0.1, MHþ), 233
(28), 232 (10), 165 (19), 137 (10), 121 (8), 109 (20), 95 (19),
85 (100), 83 (11).
3.1.6. Cyclohexylmethyl)thiobenzene 8. Tributylphos-
phine (7.6 mL, 29.3 mmol) was added to a stirred mixture
of cyclohexylmethanol 7 (1.3 mL, 10.6 mmol) and diphenyl-
disulfide (6.598 g, 31.2 mmol) in pyridine (4.3 mL) at
ambient temperature under N2-atm. The resulting mixture

A. K. Bakkestuen, L.-L. Gundersen / Tetrahedron 59 (2003) 115–121
119
3.1.9. (S)-(2)-2,2-Dimethyl-6-methylene-1-[10-(phenyl-
thio)methyl]cyclohexane 12a. A mixture of (S)-(þ)-2,2-
dimethyl-6-methylene-1-cyclohexanemethanol 11a (639 mg,
4.1 mmol) and diphenyldisulfide (1.174 g, 5.4 mmol) in
pyridine (8 mL) was stirred at ambient temperature for 1 h
before tributylphosphine (1.4 mL, 5.4 mmol) was added.
After stirring for an additional 15 h, diethyl ether (100 mL)
and water (25 mL) were added and the phases separated.
The organic extract was washed with 10% HCl(aq) (25 mL),
10% NaOH(aq) (25 mL) and brine (25 mL), dried (MgSO4)
and evaporated in vacuo. The product was purified by
flash chromatography eluting with acetone–hexane (1:100);
yield 923 mg (90%), colourless liquid [Found: C, 78.17; H,
9.02. C16H22S requires C, 77.99; H, 9.00%]; [a]D¼255.1
(c 2.0, CHCl3); dH (500 MHz, CDCl3) 0.82 (3H, s, CH3),
0.90 (3H, s, CH3), 1.11–1.25 (2H, m, H-3 or H-4), 1.35–
1.45 (2H, m, H-3 or H-4), 1.97–2.11 (3H, m, H-1 and H-5),
2.94 (1H, t, J¼11.4 Hz, CHaHbS), 3.09 (1H, dd, J¼11.4,
3.7 Hz, CHaHbS), 4.61 (1H, d, J¼1.3 Hz, vCHaHb), 4.82
(1H, br s, vCHaHb), 7.06–7.09 (1H, m, Ph), 7.17–7.20
(2H, m, Ph), 7.24–7.26 (2H, m, Ph); dC (50 MHz, CDCl3)
23.5 (CH2), 25.4 (CH3), 28.4 (CH3), 32.0 (CH2S), 32.7
(C-5), 35.5 (C-2), 36.9 (CH2), 53.1 (C-1), 110.3 (vCH2),
125.5 (CH in Ph), 128.68 (CH in Ph), 128.73 (CH in Ph),
137.8 (C in Ph), 147.3 (C-6); m/z (EI) 246 (137, Mþ), 137
(22), 136 (53), 123 (100), 121 (19), 109 (16), 95 (17), 93
(18), 81 (32).
3.1.12. (R)-(2)-1-[10-(Benzenesulfonyl)methyl]-2,2-di-
methyl-6-methylenecyclohexane 13b. The title compound
was prepared from (R)-(þ)-2,2-dimethyl-6-methylene-1-
[10-(phenylthio)methyl]cyclohexane 12b as described for
the enantiomer 13a above; yield 86% [Found: C, 69.36; H,
7.94. C16H22O2S requires C, 69.02; H, 7.96%]; [a]D¼
210.9 (c 3.9, CHCl3).
3.1.13. (10S)-(2E,6E)-9-Benzenesulfonyl-9-(2,2-dimethyl-
6-methylenecyclohexyl)-3,7-dimethyl-1-(tetrahydro-2-
pyranyloxy)-2,6-nonadiene 14a and the 10R-isomer 14b.
n-Butyllithium (1.20 mL, 1.5 M sol., 1.80 mmol) was added
dropwise to a stirred solution of (S)-(þ)-1-[10-(benzene-
sulfonyl)methyl]-2,2-dimethyl-6-methylenecyclohexane 13a
or (R) enantiomer 13b (240 mg, 0.86 mmol) in THF
(10 mL) at 08C under N2-atm. and the resulting mixture
was stirred at 08C for 1 h before a solution of crude (2E,6E)-
3,7-dimethyl-1-(tetrahydro-2-pyranyloxy)-2,6-octadien-8-yl
4-methylbenzenesulfonate 6 (420 mg, ca. 1.00 mmol) and
DMPU (1.3 mL, 10.8 mmol) in THF (5 mL). The reaction
mixture was stirred for 16 h while reaching ambient
temperature. Diethyl ether (50 mL) was added and the
mixture was washed with sat. NH4Cl(aq) (25 mL), water
(10 mL) and brine (25 mL), dried (MgSO4) and evaporated
in vacuo. The product was purified by flash chromatography
eluting with acetone–hexane (1:5); to give the compounds
14a or 14b as a mixture of stereoisomers containing ca. 20%
of starting material 13a or 13b. Further purification gave
analytical samples as colourless liquids [14a: Found: C,
72.34; H, 8.97; 14b: [Found: C, 72.18; H, 8.85 C31H46O4S
requires C, 72.33; H, 9.01%]. Spectral data for the isomeric
mixtures: dH (500 MHz, CDCl3) 0.80–0.88 (m), 0.96 (s,
CH3) 0.97 (s, CH3), 1.00 (s, CH3), 1.07 (s, CH3), 1.09 (s,
CH3), 1.12 (s, CH3), 1.16–1.26 (m), 1.35–1.40 (m), 1.47–
1.56 (m), 1.61 (s, CH3), 1.66–1.71 (m), 1.76–1.85 (m),
1.88–2.04 (m), 2.12–2.23 (m), 2.28–2.34 (m), 2.45–2.51
(m, H-10), 2.59–2.62 (m), 2.67–2.73 (m), 3.14 (bs, H-10),
3.45–3.51 (m, CH2O in THP and CHaHbSO2Ph), 3.68–3.71
(m, CHaHbSO2Ph) 3.83–3.88 (m, CH2O in THP), 3.93–
3.99 (m, H-1), 4.17–4.22 (m, H-1), 4.58–4.59 (m, CHO in
THP), 4.73 (br s, CH2v), 5.01 (br s, CH2v), 5.03 (br s,
CH2v), 5.08–5.10 (m, H-6), 5.16 (m, H-6), 5.28–5.32 (m,
H-2), 7.44–7.47 (m, Ph), 7.49–7.54 (m, Ph), 7.55–7.59 (m,
Ph), 7.76–7.77 (m, Ph), 7.82–7.83 (m, Ph); dC (50 MHz,
CDCl3) 14.6 (CH3, H-7), 15.3 (CH3, H-7), 16.29 (CH3, H-3
or H-7), 16.31 (CH3, H-3 or H-7), 16.4 (CH3, H-3 or H-7),
19.55 (CH2), 19.60 (CH2), 19.62 (CH2), 22.2, (CH2), 23.2
(CH2), 25.4 (CH2), 26.11 (CH2), 26.14 (CH2), 26.2 (CH2),
27.5 (CH3), 28.6 (CH3), 29.1 (CH3), 29.9 (CH3), 30.64
(CH2), 30.7, (2£CH2), 33.3 (CH2), 34.0 (CH2), 34.3 (C-11),
34.85 (C-11), 34.86 (C-11), 34.87 (C-11), 35.8 (CH2), 36.8
(CH2), 37.43 (CH2), 37.44 (CH2), 38.7 (CH2), 38.9 (CH2),
39.1 (CH2), 47.8 (C-10), 51.9 (C-10), 62.20 (C-6 in THP),
62.29 (C-6 in THP), 62.31 (CHSO2Ph), 62.33 (CHSO2Ph),
62.4 (CHSO2Ph), 63.56 (C-1), 63.59 (C-1), 63.62 (C-1),
63.64 (C-1), 97.87 (C-2 in THP), 97.91 (C-2 in THP), 97.92
(C-2 in THP), 98.0 (C-2 in THP), 114.1 (CH2v), 116.2
(CH2v), 120.9 (C-2), 121.0 (C-2), 127.6 (C-6), 128.1 (CH
in Ph), 128.5 (CH in Ph), 128.8 (CH in Ph), 128.9 (CH in
Ph), 129.6 (C-6), 129.7 (C-6), 129.99 (C-7), 130.00 (C-7),
130.01 (C-7), 130.6 (C-7), 132.8 (CH in Ph), 133.0 (CH in
Ph), 139.4 (C-3), 139.5 (C-3), 139.6 (C-3), 139.7 (C-3),
141.05 (C in Ph), 141.06 (C in Ph), 144.4 (CvCH2), 146.3
3.1.10. (R)-(1)-2,2-Dimethyl-6-methylene-1-[10-(phenyl-
thio)methyl]cyclohexane 12b. The title compound was
prepared from (R)-(2)-2,2-dimethyl-6-methylene-1-cyclo-
hexanemethanol 11b as described for the enantiomer 12a
above; yield 91% [Found: C, 78.06; H, 9.11. C16H22S
requires C, 77.99; H, 9.00%]; [a]D¼þ56.5 (c 2.0, CHCl3).
3.1.11. (S)-(1)-1-[10-(Benzenesulfonyl)methyl]-2,2-di-
methyl-6-methylenecyclohexane 13a. A solution of
oxone (3.241 g, 10.5 mmol) in water (15 mL) was added
to a0 stirred solution of (S)-(2)-2,2-dimethyl-6-methylene-
1-[1 -(phenylthio)methyl]cyclohexane
12a
(886 mg,
3.5 mmol) in methanol (15 mL) at 08C. When the addition
was complete, the cooling bath was removed and the
reaction mixture was stirred for 3 h at ambient temperature
before diethyl ether (100 mL) was added and the resulting
mixture was washed with water (75 mL) and brine (25 mL),
dried (MgSO4) and evaporated in vacuo. The product was
purified by flash chromatography eluting with acetone–
hexane (1:5); yield 796 mg (81%), colourless crystals, mp
38–398C [Found: C, 68.76; H, 7.85. C16H22O2S requires
C, 69.02; H, 7.96%]; [a]D¼þ10.8 (c 2.1, CHCl3); dH
(500 MHz, CDCl3) 0.75 (3H, s, CH3), 0.87 (3H, s, CH3),
1.27–1.29 (2H, m, H-3), 1.46–1.48 (2H, m, H-4), 1.92–
2.00 (2H, m, H-5), 2.40–2.42 (1H, dd, J¼9.5, 2.5 Hz, H-1),
3.22 (1H, dd, J¼14.8, 2.5 Hz, CHaHbSO2), 3.32 (1H,
J¼14.8, 9.5 Hz, CHaHbSO2), 4.53 (1H, br s, vCHaHb), 4.71
(1H, br s, vCHaHb), 7.49–7.52 (2H, m, Ph), 7.58–7.62
(1H, m, Ph), 7.85–7.87 (2H, m, Ph); dC (50 MHz, CDCl3)
23.2 (C-4), 24.9 (CH3), 27.8 (CH3), 32.9 (C-5), 35.3 (C-2),
37.2 (C-3), 47.7 (C-1), 54.4 (CH2SO2), 110.9 (CH2v),
128.2 (CH in Ph), 129.0 (CH in Ph), 133.4 (CH in Ph), 140.0
(C in Ph), 145.6 (C-6); m/z (EI) 278 (0.12, Mþ), 137 (51),
136 (100), 121 (34), 107 (12), 95 (22), 93 (35), 81 (34), 77
(21), 69 (28).

120
A. K. Bakkestuen, L.-L. Gundersen / Tetrahedron 59 (2003) 115–121
(CvCH2); m/z (EI) 514 (0.22, Mþ), 271 (31), 238 (54), 193
(43), 166 (27), 165 (100), 147 (44), 93 (28), 85 (43), 81 (34),
55 (30).
3.1.17. (R)-(2)-(2E,6E)-9-(2,2-Dimethyl-6-methylene-
cyclohexyl)-3,7-dimethyl-2,6-nonadien-1-ol 16b. The
title compound was prepared from (2E,6E)-9-(2,2-
dimethyl-6-methylenecyclohexyl)-3,7-dimethyl-1-(tetra-
hydro-2-pyranyloxy)-2,6-nonadiene 15b as described for
the enantiomer 16a above; yield 82% [Found: C, 82.93; H,
11.91. C20H34O requires C, 8269; H, 11.80%]; [a]D¼215
(c 2.6, CHCl3).
3.1.14. (10S)-(2E,6E)-9-(2,2-Dimethyl-6-methylenecyclo-
hexyl)-3,7-dimethyl-1-(tetrahydro-2-pyranyloxy)-2,6-
nonadiene 15a. A mixture of (10S)-(2E,6E)-9-benzene-
sulfonyl-9-(2,2-dimethyl-6-methylenecyclohexyl)-3,7-di-
methyl-1-(tetrahydro-2-pyranyloxy)-2,6-nonadiene 14a
(333 mg, cont. ca. 20% of comp. 13a), Na2HPO4 (2.755 g,
19.4 mmol), sodium (617 mg, 26.8 mmol) and ethanol
(2.3 mL, 39 mmol) in THF (50 mL) was stirred at ambient
temperature for 16 h, before the mixture was filtered and
the filtrate was diluted with diethyl ether (100 mL). The
resulting mixture was washed with water (100 mL), sat.
NH4Cl(aq) (25 mL) and brine (25 mL), dried (MgSO4) and
evaporated in vacuo. The product was purified by flash
chromatography on silica gel containing 20%(w/w) AgNO3
eluting with EtOAc–hexane (1:15); yield 126 mg (39%
from compound 13a), of the title compound as a
diastereomeric mixture, colourless liquid [Found: C, 79.91
H, 11.27. C25H42O2 requires C, 80.16; H, 11.30%]; dH
(500 MHz, CDCl3) 0.81 (3H, s, CH3), 0.88 (3H, s, CH3),
1.15–1.23 (1H, m), 1.56 (3H, br s, CH3), 1.33–1.63 (10H,
m), 1.66 (3H, br s, CH3), 1.63–1.75 (3H, m), 1.77–1.85 (m,
1 H), 1.85–2.00 (2H, m), 2.01–2.05 (2H, m), 2.05–2.11
(2H, m, H-5), 3.47–3.51 (1H, m, H-6a in THP), 3.85–
3.89 (1H, m, H-6b in THP), 4.01 (1H, dd, J¼11.9,
7.5 Hz, CHaHbOTHP), 4.21 (1H, dd, J¼11.9, 6.4 Hz,
CHaHbOTHP), 4.51 (1H, d, J¼2.5 Hz, vCHaHb), 4.59–
4.61 (1H, t, J¼3.8 Hz, H-2 in THP), 4.72 (1H, br s,
vCHaHb), 5.05–5.08 (1H, t, J¼6.6 Hz, H-6), 5.33–5.35
(1H, dd, J¼7.5, 6.4 Hz, H-2); dC (50 MHz, CDCl3) 16.1
(CH3), 16.4 (CH3), 19.6 (CH2 in THP), 23.7 (CH2), 24.7
(CH2), 25.5 (CH2 in THP), 26.3 (CH2 and CH3), 28.4 (CH3),
30.7 (CH2), 32.5 (CH2), 34.8 (CCH3), 36.3 (CH2), 38.2
(C-8), 39.7 (C-4), 53.6 (C-1 in cyclohexyl), 62.3 (C-6 in
THP), 63.6 (C-1), 97.8 (C-2 in THP), 108.8 (CH2v), 120.5
(C-2), 123.6 (C-6), 135.8 (C-7), 140.3 (C-3), 149.3
(CvCH2); m/z (EI) 374 (1, Mþ), 272 (13), 177 (20), 175
(19), 149 (16), 123 (13), 109 (16), 95 (17), 85 (100), 81 (26),
69 (16).
Acknowledgements
The Norwegian Research Council is greatly acknowledged
for partial financing of the Bruker Avance instruments used
in this study. Antimycobacterial data were provided by the
Tuberculosis Antimicrobial Acquisition and Coordinating
Facility (TAACF) through a research and development
contract with the US National Institute of Allergy and
Infectious Diseases. We are grateful for all help provided by
Dr Cecil Kwong and his co-workers.
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