A chemoenzymatic synthesis of the linear triquinane (-)-hirsutene and identification of possible precursors to the naturally occurring (+)-enantiomer

Article abstract of DOI:10.1016/j.tet.2003.10.122

An enantiomerically pure cis-1,2-dihydrocatechol, which is readily obtained via a toluene dioxygenase-mediated dihydroxylation of toluene in a whole-cell biotransformation process, has been converted over 17 steps into the linear triquinane (-)-hirsutene. Since the enantiomer of the starting material is also available this work constitutes a formal total synthesis of the naturally occurring (+)-form of hirsutene. Furthermore, minor modifications of the route used here offer the possibility of accessing (+)-hirsutene from the original starting material.

Full text of DOI:10.1016/j.tet.2003.10.122

Tetrahedron 60 (2004) 535–547
A chemoenzymatic synthesis of the linear triquinane
(2)-hirsutene and identification of possible precursors to the
naturally occurring (1)-enantiomer
*
Martin G. Banwell, Alison J. Edwards, Gwion J. Harfoot and Katrina A. Jolliffe
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
Received 18 August 2003; revised 7 October 2003; accepted 24 October 2003
Abstract—An enantiomerically pure cis-1,2-dihydrocatechol, which is readily obtained via a toluene dioxygenase-mediated dihydroxyl-
ation of toluene in a whole-cell biotransformation process, has been converted over 17 steps into the linear triquinane (2)-hirsutene. Since
the enantiomer of the starting material is also available this work constitutes a formal total synthesis of the naturally occurring (þ)-form of
hirsutene. Furthermore, minor modifications of the route used here offer the possibility of accessing (þ)-hirsutene from the original starting
material.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The linear triquinane-type1 sesquiterpene (þ)-hirsutene
[(þ)-1)]2 is the biogenetic precursor to a range of
oxygenated derivatives, including hirsutic acid C,3 compli-
catic acid,3 coriolin4 and hypnophilin,5 many of which
display significant biological properties. As such, this
hydrocarbon has been a popular synthetic target and many
ingenious approaches to it have been devised.1,6 Remark-
ably, only one enantioselective total synthesis of (þ)-
hirsutene has been achieved,6a although others have claimed
2. Results and discussion
formal preparations6b,c,e of the same target. Weinges et al.
have reported7 the synthesis of the non-natural (2)-
The retrosynthetic analysis of (2)-hirsutene [(2)-1)]
employed in the present work is shown in Figure 1. Thus,
the closing stages of the synthesis would involve reductive
cleavage of the three-membered ring associated with the
cyclopropa-fused triquinane 3, followed by deletion of the
carbonyl group and, finally, manipulation of the protected
hydroxyl group so as to install the exocyclic methylene unit
associated with target 1. Formation of compound 3 was to
involve a photochemically-induced oxa-di-p-methane
rearrangement of the cyclopentannulated bicyclo[2.2.2]-
oct-5-en-2-one 4, a protocol for triquinane synthesis
originally enunciated by Demuth1c and recently exploited
by Singh et al.6e in their preparation of (^)-hirsutene.
Compound 4 was, in turn, to be generated via a Diels–Alder
cycloaddition reaction between cis-1,2-dihydrocatechol 2
and the gem-dimethylated cyclopentenone 5, the last
compound being available by established routes13 from
the dimethylketene dimer 6.
enantiomer 1 from (2)-carvone using Curran’s tandem
radical cyclization strategy8 as a key element. Herein we
report full details of our recently communicated9 synthesis
of (2)-hirsutene (1) from the cis-1,2-dihydrocatechol 2, a
compound available in enantiomerically pure form via the
toluene dioxygenase (TDO)-mediated whole-cell bio-
transformation of toluene.10 Since the enantiomeric form
of this starting material, viz. ent-2, is also available11 the
present work constitutes a formal total synthesis of (þ)-
hirsutene, viz. (þ)-1. Moreover, minor modifications to the
route used here (and discussed below) would appear to offer
the possibility that compound 2 could also serve as a
precursor to (þ)-hirsutene, thus highlighting the potential
for the enantiodivergent synthesis of various terpenoids
from this readily available chiron.12
Keywords: Chemoenzymatic; Hirsutene; Sesquiterpene; Triquinane; Oxa-
di-p-methane;
Dihydrocatechol.
*
Enantiodivergence;
Cycloaddition;
cis-1,2-
On the basis of recent studies carried out in our laboratories
(and to be reported shortly), we anticipated that a high
pressure promoted Diels–Alder reaction between diene 2
Corresponding author. Tel.:þ61-2-6125-8202; fax:þ61-1-6125-8114;
e-mail address: mgb@rsc.anu.edu.au
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.122

536
M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
Figure 1.
and dienophile 5 should proceed efficiently and in a syn-
selective fashion.14,15 However, all efforts to implement
such a reaction failed to produce preparatively useful
quantities of the desired cycloaddition product or any other
adduct. On the basis that the steric inhibition to this process
caused by the gem-dimethyl unit of the dienophile could be
offset by further carbonyl activation, the reaction of the
readily available cyclopentenedione 8 with diene 2 at
19 kbar was examined (Scheme 1). Gratifyingly, the
anticipated adduct 9 was obtained and its structure
established by X-ray crystallographic studies, details of
which will be reported elsewhere. The readily derived
acetonide 10 (100%) was prepared in anticipation of
examining protocols for the reductive removal, via the
corresponding alcohols, of the two now redundant ketone
carbonyl units associated with the Diels–Alder adduct.
Exposure of compound 10 to various reducing agents led to
varying combinations (Table 1) of some or all of the four
possible diols 11–14, the first three of which could be
purified and then subjected to comprehensive
characterization.
Compound 11 was obtained as a crystalline solid such that
an X-ray crystallographic analysis could be undertaken, the
results of which are presented in Figure 2 and the
Experimental section. Unfortunately, all efforts to exploit
this diol in the required deoxygenation process have failed.
Thus, the derived bis-mesylate 15 only produced complex
mixtures of products on exposure to hydride donors such as
lithium aluminium hydride while the derived bis-xanthate
Scheme 1.

M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
Table 1. Product distributions from reduction of dione 10 under various conditions
537
Entry
Reductant/conditions
% Diol 11
% Diol 12
% Diol 13
% Diol 14
1
2
3
LiAlH4, THF, D
LiAlH4, Et2O, D
DIBALH, THF, 278 8C
10
28
99
75
31
0
5
26
0
9
10
0
diol moiety associated with compound 21 was protected,
using standard methods, as the corresponding acetonide 22
(98%) which could then be subjected to gem-dimethylation
at C6 using LiHMDS as base and methyl iodide as the
alkylating agent. The resulting ketone 23 (100%) was
reduced with lithium aluminium hydride to give a
chromatographically separable and 9:1 mixture of the two
epimeric forms of alcohol 24 (99% combined yield) which
were each converted into their respective xanthates by
standard methods and in essentially quantitative yield. In
contrast to the difficulties detailed earlier, these esters each
underwent a smooth Barton–McCombie deoxygenation
reaction to give the, by now, long sought after compound 25
(57%). As observed in related systems,18 acid-catalysed
removal of the acetonide group within this latter compound
proved a sluggish process and even when forcing conditions
and extended reaction times were used, complete conver-
sion of substrate 25 into diol 26 (95% at 44% conversion)
could not be achieved. Nevertheless, preparatively useful
quantities of compound 26 were available by such means
and the less hindered hydroxy group associated with this
compound could be selectively oxidized to the correspond-
ing ketone using the sterically demanding oxoammonium
ion derived from 4-acetamido-TEMPO.19 The acyloin 27
(91% at 96% conversion) thus obtained proved rather
unstable and the product resulting from its oxa-di-p-
methane rearrangement was even more so. Consequently,
compound 27 was protected as the corresponding and now
completely stable MEM-ether20 28 (91%).
Figure 2. ADEP derived from single-crystal X-ray analysis of diol 11.
suffered a similar fate during attempts to engage it in
Barton–McCombie-type deoxygenation16 processes. The
related bis-triflate could not be isolated but underwent two-
fold elimination under the conditions of its formation and
thus providing the cyclopentadiene 17 (42%) as the only
isolable reaction product. In principle, this triene could be
subjected to a selective dihydrogenation reaction so as to
provide a product capable of being carried forward to (2)-1,
but the issues of regio- and stereo-selectivity that would
need to be addressed in achieving such ends looked too
formidable to warrant serious consideration. In a final
attempt to effect deoxygenation, the bis-mesylate, 18,
derived from diol 12 was subject to reaction with lithium
triethylborohydride (Super-Hydridew) but the only product
of reaction was the fragmentation product 19 (100%) the
structure of which follows from detailed NMR spectro-
scopic analysis, including the use of NOESY techniques,
which revealed an interaction between H6 and the bridge-
head methyl protons. The formation of compound 19 from
precursor 18 highlights the potential for fragmentation
during attempts to reductively deoxygenate 1,3-dioxy-
genated systems17 and led us to abandon this approach to
substrates (viz. 4, Fig. 1) suitable for studying the
foreshadowed oxa-di-p-methane rearrangement.
Subjection of compound 28 to triplet sensitized photolysis
resulted in the anticipated oxa-di-p-methane rearrangement
process and thus provided the tetracyclic product 29 (80% at
71% conversion) as a crystalline solid suitable for single
crystal X-ray analysis, results of which have been reported
previously.9 Whilst a number of methods are available for
the reductive cleavage of carbonyl-conjugated cyclopropyl
groups21 we favored one using tri-n-butyltin hydride22 as
successfully employed by Singh et al. in their recently
reported6e synthesis of (^)-hirsutene. Thus, treatment of
compound 29 with this hydride in the presence of AIBN
resulted in smooth reduction to the triquinane 30 (87% at
81% conversion) the carbonyl group of which was reduced,
with sodium borohydride, to the corresponding alcohol
(98%) which was obtained as a single diastereoisomer and
presumably that possessing a b-hydroxy group as a result of
hydride delivery to the exo-face of the precursor ketone. The
readily derived xanthate ester (92%) was then deoxygenated
under Barton–McCombie conditions to give the MEM-
ether 31 (92% from 30). Cleavage of the MEM-group within
the latter compound could be achieved under the conditions
described by Monti et al.23 and so affording the extremely
volatile and, therefore, refractory alcohol 32 (76%), the
racemic form of which has been employed in previous
syntheses of (^)-hirsutene. PCC-promoted oxidation of
The ultimately successful route to (2)-hirsutene [(2)-1] is
shown in Scheme 2 and the abovementioned problems were
addressed by reverting to a protocol that avoids the need for
using a 1,3-deoxygenation regime but now requiring a gem-
dimethylation step after the Diels–Alder cycloaddition
reaction. Thus, cis-1,2-dihydrocatechol 2 was reacted with
cyclopentenone 20 at 19 kbar and the syn-addition product
21 (70%) was obtained, together with small quantities (ca.
9%) of the corresponding anti-isomer. These adducts were
readily separated by flash chromatography and the structure
of the former established by single-crystal X-ray analysis,
details of which will be published elsewhere. The cis-1,2-

538
M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
Scheme 2.
compound 32 afforded the corresponding ketone 33 (71%),
which also proved a difficult compound to handle because of
its high vapor pressure. In the final step of the synthesis
compound 33 was methylenated using methylene tri-
phenylphosphorane under standard conditions. The
sterically hindered nature of ketone 33 led to difficulties in
driving this reaction to completion with the result that whilst
near quantitative yields of target 1 were obtained this could
only be accomplished at modest (32%) conversions.
Nevertheless, by such means, very clean samples of (2)-
hirsutene could be obtained and the derived spectral data
were in complete accord with the assigned structure and a
good match for the excellent data presented by Weinges
et al.7 In particular, there was excellent agreement between
the specific rotations, viz. [a]D¼226 (c 0.2, CDCl3) vs
[a]D¼229.4 (c 1.0, pentane).7
regarded as pseudo-enantiomers, each of which is accessible
from the common precursor 2 by controlling the facial
selectivity of its reaction with the dienophile 20. Such
control is achieved by simply employing either the
As noted earlier, since the enantiomer of cis-1,2-dihydro-
catechol 2 is known,11 the present work also represents a
formal total synthesis of the naturally occurring or (þ)-form
of hirsutene. However, there are also interesting possi-
bilities for accessing (þ)-hirsutene from compound 2 itself.
In particular, we have observed (Fig. 3) that the known24
acetonide derivative, 34, of diol 2 engages in an efficient
high pressure-promoted Diels–Alder cycloaddition reaction
with cyclopentenone 20 to give the adduct 35 in 56% yield
and incorporating a bicyclo[2.2.2]oct-5-en-2-one residue
that is enantiomerically related to the one associated with
isomer 22. In other words, compounds 20 and 35 can be
Figure 3.

M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
539
unprotected or protected forms of 2 in the Diels–Alder
reaction. Given the foregoing and considering the appli-
cation of the chemistry defined in Scheme 2 to adduct 35, it
might reasonably be anticipated that the acyloin 36 (Fig. 3)
could be obtained and that this would engage in an oxa-di-
p-methane rearrangement, thus, delivering the cyclopropa-
fused triquinane 37, a pseudo-enantiomer of compound 29
and a seemingly realistic precursor to (þ)-1. The pursuit of
such possibilities will be the subject of further reports from
these laboratories although it is already clear from earlier
work, described by us,12b,c,18,25 that the cis-1,2-dihydro-
catechol 2 offers significant opportunities for the enantio-
divergent synthesis of a range of biologically relevant
carbocyclic frameworks. A further noteworthy aspect of the
work described in Schemes 1 and 2 is that the strategies and
chemistries defined therein should lend themselves to the
synthesis of various oxygenated and, therefore, biologically
interesting linear triquinane-type natural products such as
those mentioned in the introduction.
d]-1,3-dioxole-5,7-dione (10).
A
magnetically stirred
solution of diol 9 (1.07 g, 4.27 mmol) in 2,2-dimethoxy-
propane (7.5 mL, 61 mmol, 14 mole equiv.) and dichloro-
methane (7.5 mL) was treated with p-TsOH·H2O (12.2 mg,
1.5 mole%) and the resulting mixture stirred at 18 8C for
24 h then concentrated under reduced pressure. Subjection
of the ensuing deep-red oil to flash chromatography (silica,
1:4 v/v ethyl acetate–hexane elution) afforded, after
concentration of the appropriate fractions (Rf 0.9 in 1:1
v/v ethyl acetate–hexane), the title compound acetonide 10
(1.24 g, 100%) as a clear, colourless oil, [a]D¼þ29 (c 0.2,
CHCl3) (Found: Mþz, 290.1524. C17H22O4 requires Mþz,
290.1518). 1H NMR (CDCl3, 300 MHz) d 6.02 (dd, J¼8.4,
6.6 Hz, 1H), 5.82 (d, J¼8.4 Hz, 1H), 4.11 (dd, J¼8.1,
3.9 Hz, 1H), 3.68 (d, J¼8.4 Hz, 1H), 3.52 (dd, J¼10.2,
3.0 Hz, 1H), 3.42–3.40 (m, 1H), 3.22 (d, J¼10.2 Hz, 1H),
1.57 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H), 1.06 (s, 3H), 0.91 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 220.4, 219.7, 138.7,
132.1, 112.5, 80.8, 75.1, 54.6, 48.0, 45.4, 42.1, 37.4, 26.9,
24.7, 23.6, 20.5, 16.8; IR, nmax 2976, 2930, 1759, 1720,
1460, 1375, 1265, 1206, 1163, 1109, 1065, 1049, 880,
710 cm21; MS, m/z (EI, 70 eV) 290 (Mþz, 11%), 275 (16),
232 (28), 189 (28), 161 (87), 134 (100), 105 (88), 100 (75),
70 (98).
3. Experimental
3.1. General
3.2.2. (3aR,4S,4aS,5R,7S,7aS,8R,8aS)-3a,4a,5,6,7,7a,
8,8a-Octahydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-
indeno[5,6-d]-1,3-dioxole-5,7-diol (11), (3aR,4S,4aS,5S,7-
R,4S,4aS,5S,7S,7aS,8R,8aS)-3a,4a,5,6,7,7a,8,8a-octa-
hydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-indeno[5,6-
d]-1,3-dioxole-5,7-diol (12), (3aR,4S,4aS,5R,7R,7aS,8-
R,4S,4aS,5R,7R,7aS,8R,8aS)-3a,4a,5,6,7,7a,8,8a-octa-
hydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-indeno[5,6-
d]-1,3-dioxole-5,7-diol (13) and (3aR,4S,4aS,5S,7R,7aS,8-
R,4S,4aS,5S,7R,7aS,8R,8aS)-3a,4a,5,6,7,7a,8,8a-octa-
hydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-indeno[5,6-
d]-1,3-dioxole-5,7-diol (14).
3.2.2.1. Method A. A magnetically stirred solution of the
dione 10 (102.6 mg, 0.35 mmol) in THF (1.7 mL) main-
tained at 278 8C (acetone-dry ice bath) was treated,
dropwise, with DIBAL-H (1.55 mL of a 1 M solution in
hexane, 0.155 mmol). After 3 h the reaction mixture was
warmed to 18 8C, stirring continued for a further 3 h, then
water (10 mL), NH4Cl (10 mL of a saturated aq. solution)
and diethyl ether (10 mL) were added (CAUTION!). The
separated aqueous phase was extracted with diethyl ether
(4£10 mL) and the combined organic phases washed with
brine (1£10 mL) then dried (MgSO4), filtered and concen-
trated under reduced pressure to give an oily solid.
Subjection of this material to flash chromatography (silica,
1:1 v/v ethyl acetate–hexane elution) afforded, after
concentration of the appropriate fractions (Rf 0.4), the title
compound diol 11 (103 mg, 99%) as a white crystalline
solid, mp 106–107 8C (with sublimation), [a]D¼þ45 (c 0.8,
CHCl3) (Found: Mþz, 294.1826. C, 69.1; H, 8.6. C17H26O4
requires Mþz, 294.1831. C, 69.4; H, 8.9%). 1H NMR
(CDCl3, 300 MHz) d 6.08 (dd, J¼8.1, 6.9 Hz, 1H), 5.88 (d,
J¼8.1 Hz, 1H), 4.11 (dd, J¼8.1, 3.9 Hz, 1H), 3.75 (d,
J¼8.1 Hz, 1H), 3.71–3.68 (m, 2H), 3.10 (ddd, J¼11.4, 6.0,
2.4 Hz, 1H), 2.95–2.92 (m, 1H), 2.81 (dd, J¼11.4, 5.7 Hz,
1H), 1.91 (broad s, 1H), 1.62 (broad s, 1H), 1.47 (s, 3H),
1.36 (s, 3H), 1.34 (s, 3H), 1.12 (s, 3H), 0.92 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 138.4, 131.6, 112.1, 84.1, 83.2,
Melting points were measured on a Reichert hot-stage
microscope apparatus and are uncorrected. Proton (1H) and
carbon (13C) NMR spectra were recorded on either a Varian
Inova 600 spectrometer operating at 600 MHz for proton or
a Gemini 300 NMR spectrometer, operating at 300 MHz
(for proton) and 75 MHz (for carbon). Unless otherwise
specified spectra were acquired at 20 8C in deuterochloro-
form (CDCl3) which had been filtered through basic
alumina prior to use. Chemical shifts were recorded as d
values in parts per million (ppm). Infrared spectra (nmax
)
were recorded on a Perkin–Elmer 1800 Series FTIR
Spectrometer and samples were analysed as thin films on
NaCl plates. Low resolution mass spectra were recorded
on a Micromass-Waters LC-ZMD single quadrupole
liquid chromatograph-MS or VG Quattro II triple quad-
rupole MS instrument using electron impact techniques.
High resolution mass spectra were acquired by liquid
secondary ion MS methods on a Kratos Analytical Concept
ISQ instrument located at the University of Tasmania.
Optical rotations were measured with a Perkin–Elmer 241
polarimeter at the sodium-D line (589 nm) and the
concentrations (c) (g 100 mL21) indicated using spectro-
scopic grade CHCl3 unless otherwise specified. The
measurements were carried out between 17 and 28 8C in a
cell with a path length (l) of 1 dm. Specific rotations [a]D
were calculated using the equation [a]D¼100 a/(c l) and are
given in 10– 1 deg cm2 g– 1. Elemental analyses were
performed by the Australian National University’s Micro-
analytical Services Unit based at the Research School of
Chemistry, Canberra, Australia. All reactions were per-
formed under a nitrogen atmosphere. Anhydrous solvents
were obtained by distillation from appropriate drying agents
under a nitrogen atmosphere.
3.2. Synthetic studies
3.2.1. (3aR,4S,4aS,7aS,8R,8aS)-3a,4a,5,6,7,7a,8,8a-Octa-
hydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-indeno[5,6-

540
M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
81.8, 76.8, 49.7, 47.5, 43.2, 40.8, 36.6, 26.8, 24.7, 24.6,
20.4, 17.8; IR, nmax 3288, 2946, 2890, 1455, 1378, 1257,
1208, 1160, 1061, 1030, 979, 876 cm21; MS, m/z (EI,
70 eV) 294 (Mþz, 2%), 279 (12), 265 (64), 194 (89), 135
(93), 134 (92), 84 (100).
3.2.2.2. Method B. A magnetically stirred solution of
dione 10 (103 mg, 0.35 mmol) in THF (20 mL) was treated
with LiAlH4 (ca 1.00 g, 26.7 mmol). The resulting mixture
was heated at reflux for 48 h then cooled and treated with
NH4Cl (10 mL of a saturated aq. solution—CAUTION!)
and the separated aqueous phase extracted with diethyl ether
(4£10 mL). The combined organic phases were washed
with brine (1£10 mL) then dried (MgSO4), filtered and
concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash chromatography
(silica, 1:4!3:7 v/v ethyl acetate–hexane gradient elution)
afforded three fractions, A–C.
indeno[5,6-d]-1,3-dioxole-5,7-diol bis-methanesulfonate
(15). A magnetically stirred solution of diol 11 (40 mg,
0.14 mmol) and pyridine (1 mL) in dichloromethane
(1.4 mL) was cooled to 0 8C (ice-water bath) then treated
with methanesulfonyl chloride (23 mL, 0.30 mmol) and
triethylamine (42 mL, 0.30 mL). The resulting mixture was
warmed to 18 8C and stirred at this temperature for 72 h,
then concentrated under reduced pressure. The residue thus
obtained was partitioned between ethyl acetate (5 mL) and
water (5 mL) and the separated aqueous phase extracted
with ethyl acetate (5£5 mL). The combined organic phases
were dried (Na2SO4), filtered and concentrated under
reduced pressure and the ensuing light-brown oil subjected
to flash chromatography (silica, 1:1 v/v ethyl acetate–
hexane elution). Concentration of the appropriate fractions
(Rf 0.5) gave the bis-mesylate 15 (45 mg, 74%) as a clear,
light-yellow oil, [a]D¼þ47 (c 0.7, CHCl3) (Found: Mþz,
1
450.1381. C19H30O8S2 requires Mþz, 450.1382). H NMR
Concentration of fraction A (Rf 0.4 in 1:1 v/v ethyl acetate–
hexane) afforded diol 11 (10 mg, 10%) identical, in all
respects, with the material obtained via Method A.
(CDCl3, 300 MHz) d 6.05 (dd, J¼8.1, 6.3 Hz, 1H), 5.86 (d,
J¼8.1 Hz, 1H), 4.94 (d, J¼6.0 Hz, 1H), 4.76 (dd, J¼6.6,
0.9 Hz, 1H), 4.09 (dd, J¼8.1, 3.9 Hz, 1H), 3.76 (d,
J¼8.1 Hz, 1H), 3.30 (ddd, J¼11.1, 6.6, 2.1 Hz, 1H), 3.05
(s, 3H), 3.05–2.97 (m, partially obscured, 2H), 2.99 (s, 3H),
1.45 (s, 3H), 1.40 (s, 3H), 1.33 (s, 3H), 1.22 (s, 3H), 1.10 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 137.3, 130.6, 112.4,
91.9, 91.4, 81.4, 76.1, 50.0, 47.7, 41.9, 40.4, 39.9, 38.8,
36.7, 27.0, 25.4, 24.7, 20.4, 19.9; IR, nmax 2980, 2936, 1373,
1334, 1207, 1170, 1063, 932, 894, 730 cm21; MS, m/z (EI,
70 eV) 450 (Mþz, 1%), 435 (6), 421 (26), 392 (14), 350 (22),
296 (15), 200 (100), 171 (47), 100 (45).
Concentration of fraction B [Rf 0.2(3) in 1:1 v/v ethyl
acetate–hexane] afforded a clear, colourless glass (40 mg)
tentatively identified as diol 12 (75 mg, 75%), [a]D¼29 (c
0.2, CHCl3) (Found: Mþz, 294.1826. C, 69.3; H, 9.2.
1
C17H26O4 requires Mþz, 294.1831. C, 69.4; H, 8.9%). H
NMR (CDCl3, 300 MHz) d 6.30 (dd, J¼8.1, 6.6 Hz, 1H),
5.82 (dm, J¼8.1 Hz, 1H), 4.09 (dd, J¼8.1, 3.9 Hz, 1H), 3.77
(d, J¼8.4 Hz, 1H), 3.66 (d, J¼6.6 Hz, 1H), 3.43 (d, J¼9 Hz,
1H), 3.07 (ddd, J¼11.1, 6.6, 2.4 Hz, 1H), 2.87–2.82 (m,
1H), 2.36–2.29 (m, 1H), 1.47 (s, 3H), 1.35 (s, 3H), 1.32 (s,
3H), 0.97 (s, 3H), 0.88 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 137.3, 135.2, 112.3, 81.7, 81.2, 80.8, 76.5, 48.7, 46.0,
41.3, 40.4, 37.2, 26.7, 24.7, 20.7, 20.4, 20.1; IR, nmax 3467,
2958, 2930, 2873, 1457, 1381, 1371, 1262, 1207, 1160,
1061, 1032, 876, 710 cm21; MS, m/z (EI, 70 eV) 294 (Mþz,
,1%), 297 (7), 265 (16), 236 (29), 194 (100), 134 (73), 84
(94).
3.2.4. (3aR,4S,4aS,5R,7S,7aS,8R,8aS)-3a,4a,5,6,7,7a,
8,8a-Octahydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-
indeno[5,6-d]-1,3-dioxole-5,7-diol bis-S-methyl xanthate
(16). A magnetically stirred mixture of diol 11 (14.4 mg,
0.05 mmol), NaH (5.8 mg of a 60% dispersion in mineral
oil, 0.15 mmol) and imidazole (two crystals) in THF (1 mL)
maintained at 18 8C was treated, after 1 h, with CS2 (18 mL,
0.30 mmol). Stirring was continued for a further 1 h then
methyl iodide (11 mL, 0.18 mmol) was added and the
resulting mixture stirred overnight at 18 8C. The reaction
mixture was quenched with acetic acid (glacial, 20 mL) then
partitioned between ethyl acetate (10 mL) and water
(10 mL) and the separated aqueous phase extracted with
ethyl acetate (3£10 mL). The combined organic phases
were washed with NaHCO3 (1£5 mL of a saturated aqueous
solution) then dried (MgSO4), filtered and concentrated
under reduced pressure. The ensuing yellow oil was
subjected to flash chromatography (silica, 1:9 v/v ethyl
acetate–hexane elution) and concentration of the appro-
priate fractions (Rf 0.9 in 1:4 v/v ethyl acetate–hexane)
gave the title compound 16 (21.1 mg, 91%) as colourless
crystals, mp 124–126 8C, [a]D¼þ49 (c 0.1, CHCl3)
(Found: Mþz, 474.1024. C21H30O4S4 requires Mþz,
474.1027). 1H NMR (CDCl3, 300 MHz) d 6.19 (d,
J¼6.3 Hz, 1H), 6.04–5.97 (complex m, 2H), 5.85 (d,
J¼8.1 Hz, 1H), 4.06 (dd, J¼8.4, 4.2 Hz, 1H), 3.73 (d,
J¼8.4 Hz, 1H), 3.39 (ddd, J¼11.1, 6.0, 2.1 Hz, 1H), 3.10
(dd, J¼11.1, 6.0 Hz, 1H), 2.99–2.95 (m, 1H), 2.62 (s, 3H),
2.59 (s, 3H), 1.47 (s, 3H), 1.32 (s, 3H), 1.17 (s, 6H), 1.17 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 216.4, 215.4, 137.6,
130.3, 112.3, 93.2, 91.9, 81.3, 76.3, 51.0, 46.7, 42.6, 40.5,
36.2, 26.9, 25.2, 24.7, 20.4, 19.4, 19.2, 18.1; IR, nmax 2966,
Concentration of fraction C [Rf 0.1(7) in 1:1 v/v ethyl
acetate–hexane] afforded an oily solid (15 mg) tentatively
identified as a ca. 4:1 mixture of diols 13 and 14 (14%). IR,
n
max 3434, 2959, 2930, 2873, 1464, 1381, 1372, 1263, 1207,
.
1164, 1155, 1082, 1045, 882, 731 cm21
The semi-solid obtained on concentration of fraction C was
triturated (ethyl acetate) to afford diol 13 (11.6 mg. 11%) as
white crystalline masses, mp 107–108 8C (with sublima-
tion), [a]D¼þ27 (c 0.1 in CHCl3) (Found: Mþz, 294.1829.
C, 69.1; H, 9.0. C17H26O4 requires 294.1831. C, 69.4; H,
1
8.9%). H NMR (CDCl3, 300 MHz) d 6.16 (t, J¼7.8 Hz,
1H), 5.90 (dm, J¼7.8 Hz, 1H), 4.15 (dd, J¼8.1, 4.2 Hz, 1H),
3.76 (d, J¼8.1 Hz, 1H), 3.22–3.13 (complex m, 2H), 2.98–
2.93 (m, 1H), 2.55–2.47 (m, 1H), 2.24 (dd, J¼11.4, 8.7 Hz,
1H), 1.47 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H), 1.27 (dd, J¼7.8,
4.5 Hz, 1H),0.96(s, 3H);13CNMR(CDCl3, 75 MHz)d139.7,
133.6,112.1,81.1, 80.9, 80.7, 76.2, 46.5, 44.0, 43.9, 41.7, 37.4,
26.7, 24.7, 24.3, 20.4, 14.8; IR, nmax 3335, 2974, 2936, 2873,
1381, 1369, 1262, 1205, 1059, 1040, 880, 748 cm21
.
3.2.3. (3aR,4S,4aS,5R,7S,7aS,8R,8aS)-3a,4a,5,6,7,7a,8,
8a-Octahydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-

M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
541
2931, 1369, 1220, 1205, 1184, 1058, 1034 cm21; MS, m/z
(EI, 70 eV) 474 (Mþz, 4%), 427 (10), 383 (16), 309 (10), 201
(43), 159 (64), 91 (100).
penyl)-4,7-ethano-1,3-benzodioxole (19). A magnetically
stirred mixture of the bis-mesylate 18 (20 mg, 0.05 mmol)
in THF (3 mL) maintained at 18 8C was treated with
LiEt3BH (178 mL of a 1 M solution in THF, 0.18 mmol).
The resulting mixture was heated at reflux for 4 h then
cooled and quenched with NH4Cl (5 mL of a saturated
aqueous solution). The resulting mixture was extracted with
ethyl acetate (4£10 mL) and the combined organic phases
washed with brine (1£2 mL) then dried (Na2SO4), filtered
and concentrated under reduced pressure. Subjection of the
ensuing light-brown oil to flash chromatography (silica, 1:4
v/v ethyl acetate–hexane elution) afforded, after concen-
tration of the appropriate fractions (Rf 0.7 in 2:3 v/v ethyl
acetate–hexane), the title dienol 19 (12.4 mg, 100%) as a
clear, colourless oil, [a]D¼þ24 (c 0.4, CHCl3) [Found:
(M2CH3z)þ, 263.1640. C17H26O3 requires (M2CH3z)þ,
263.1647]. 1H NMR (CDCl3, 300 MHz) d 6.14 (t,
J¼7.7 Hz, 1H), 5.86 (d, J¼8.1 Hz, 1H), 4.92 (dt, J¼11.5,
1.2 Hz, 1H), 4.08 (dd, J¼8.1, 3.6 Hz, 1H), 3.78 (d,
J¼8.1 Hz, 1H), 3.43 (d, J¼11.1, 8.5 Hz, 1H), 3.24 (dd,
J¼11.1, 6.8 Hz, 1H), 3.10 (t, J¼11.1 Hz, 1H), 2.76–2.60
(complex m, 2H), 1.71 (d, J¼1.1 Hz, 3H), 1.71–1.63 (m,
partially obscured, 1H), 1.67 (d, J¼1.2 Hz, 3H), 1.55 (s,
3H), 1.34 (s, 3H), 1.07 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 138.7, 135.2, 132.1, 124.5, 112.0, 80.7, 76.2, 64.7, 42.6,
39.0, 38.5, 37.8, 26.6, 26.2, 24.8, 20.5, 18.5; IR, nmax 3436,
2963, 2927, 1452, 1373, 1262, 1207, 1061, 1045, 875,
711 cm21; MS, m/z (EI, 70 eV) 278 (Mþz, 1%), 263 (11),
220 (30), 147 (32), 112 (100), 94 (92), 79 (46), 69 (38), 56
(60).
3.2.5. (3aR,4S,8R,8aS)-3a,6,8,8a-Tetrahydro-2,2,4,6,6-
pentamethyl-4,8-etheno-6H-indeno[5,6-d]-1,3-dioxole
(17). A chilled (ice-water bath) magnetically stirred solution
of diol 11 (50.4 mg, 0.17 mmol) and 2,6-di-tert-butyl-4-
methylpyridine (169 mg, 0.82 mmol) in dichloromethane
(3 mL) was treated with triflic anhydride (64 mL,
0.38 mmol). The reaction mixture was then allowed to
warm to 18 8C and after 48 h treated with triethylamine
(1 mL) then water (10 mL) and dichloromethane (10 mL).
The separated aqueous phase was extracted with dichloro-
methane (4£10 mL) and the combined organic phases
washed with brine (1£5 mL) before being dried (Na2SO4),
filtered and concentrated under reduced pressure. The light-
brown residue thus obtained was subject to flash chroma-
tography (silica, 0:1!1:19 v/v ethyl acetate–hexane
gradient elution) and concentration of the appropriate
fractions (Rf 0.9 in 1:1 v/v ethyl acetate–hexane elution)
afforded the title triene 17 (18.6 mg, 42%) as a clear,
colourless oil (Found: Mþz, 258.1620. C17H22O2 requires
1
Mþz, 258.1620). H NMR (CDCl3, 300 MHz) d 6.25 (dd,
J¼8.0, 6.3 Hz, 1H), 5.96 (dd, J¼8.0, 1.0 Hz, 1H), 5.77
(broadened s, 1H), 5.68 (broadened s, 1H), 4.34 (dd, J¼7.7,
4.0 Hz, 1H), 4.03 (d, J¼7.7 Hz, 1H), 3.62–3.58 (m, 1H),
1.43 (s, 3H), 1.29 (4) (s, 3H), 1.28 (5) (s, 3H), 1.25 (s, 3H),
1.11 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 144.7, 141.0,
139.3, 135.0, 133.7, 132.7, 112.3, 82.0, 77.6, 55.5, 43.5,
40.1, 26.5, 24.8, 23.3, 23.2, 17.3; IR, nmax 2978, 2931, 1740,
1701, 1461, 1381, 1266, 1207, 1064, 706 cm21; MS, m/z
(EI, 70 eV) 258 (Mþz, 6%), 243 (8), 200 (8), 171 (90), 158
(100), 156 (46), 143 (34), 141 (25).
3.2.8. (3aR,4S,4aS,7aS,8R,8aS)-3a,4,4a,6,7,7a,8,8a-Octa-
hydro-2,2,4-trimethyl-4,8-etheno-5H-indeno[5,6-d]-1,3-
dioxol-5-one (22). A magnetically stirred solution of diol 21
(2.38 g, 11.5 mmol) and p-TsOH·H2O (24.6 mg, 0.13
mmol) in dichloromethane (20 mL) maintained at 0 8C was
treated with 2,2-dimethoxypropane (10 mL, 81.3 mmol).
The resulting mixture was stirred at 0 8C for 3 h then
warmed to 18 8C and maintained at this temperature for
72 h. The reaction mixture was then concentrated under
reduced pressure and the ensuing deep-red residue subjected
to flash chromatography (silica, 1:4!3:7 v/v ethyl acetate–
hexane gradient elution). Concentration of the appropriate
fractions (Rf 0.7 in 1:1 v/v ethyl acetate–hexane) afforded
the title acetonide 22 (2.80 g, 98%) as a clear, colourless oil,
[a]D¼2122 (c 0.6, CHCl3) (Found: Mþz, 248.1412. C, 72.6;
H, 8.1. C15H20O3 requires Mþz, 248.1412. C, 72.6; H, 8.1%).
1H NMR (CDCl3, 300 MHz) d 6.17 (dd, J¼8.1, 6.6 Hz, 1H),
5.84 (dd, J¼8.1, 0.9 Hz, 1H), 4.07 (dd, J¼9.0, 3.9 Hz, 1H),
3.70 (d, J¼8.1 Hz, 1H), 3.13–3.05 (m, 1H), 2.89–2.85 (m,
1H), 2.55 (d, J¼9.0 Hz, 1H), 2.15–1.95 (complex m, 3H),
1.58–1.48 (complex m, 1H), 1.49 (s, 3H), 1.45 (s, 3H), 1.33
(s, 3H); 13C NMR (CDCl3, 75 MHz) d 222.5, 138.5, 132.1,
112.2, 80.9, 76.2, 49.9, 42.3, 41.4, 39.7, 32.8, 26.7, 25.1,
24.8, 19.9; IR, nmax 2987, 2962, 2933, 2904, 2880, 1731,
1458, 1381, 1372, 1261, 1207, 1165, 1067, 1050, 1034, 879,
715 cm21; MS, m/z (EI, 70 eV) 248 (Mþz, 6%), 233 (20),
190 (47), 161 (58), 134 (68), 119 (56), 105 (100), 100 (95),
91 (76), 75 (75).
3.2.6. (3aR,4S,4aS,5R,7R,7aS,8R,8aS)-3a,4a,5,6,7,7a,
8,8a-Octahydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-
indeno[5,6-d]-1,3-dioxole-5,7-diol bis-methanesulfonate
(18). Reaction of diol 12 (26 mg, 0.09 mmol) with
methanesulfonyl chloride (15 mL, 22 mg, 0.19 mmol,
2.2 mole equiv.) under the same conditions as employed
during the conversion 11!15 (see above) afforded a light-
brown oil on work-up. Subjection of this material to flash
chromatography (silica, 1:4 v/v ethyl acetate–hexane
elution) afforded, after concentration of the appropriate
fractions (Rf 0.6), the title bis-mesylate 18 (29 mg, 75%) as a
clear, colourless oil, [a]D¼þ36 (c 0.3, CHCl3) (Found: Mþz,
1
450.1380. C19H30O8S2 requires Mþz, 450.1382). H NMR
(CDCl3, 300 MHz) d 6.27 (dd, J¼8.4, 6.6 Hz, 1H), 5.78 (d,
J¼8.1 Hz, 1H), 4.73 (d, J¼6.6 Hz, 1H), 4.65 (d, J¼9.3 Hz,
1H), 4.08 (dd, J¼8.1, 3.9 Hz, 1H), 3.79 (d, J¼8.1 Hz, 1H),
3.27 (ddd, J¼11.4, 6.9, 2.4 Hz, 1H), 3.06 (s, 3H), 3.00–2.95
(m, 1H), 2.99 (s, 3H), 2.71–2.64 (m, 1H), 1.48 (s, 3H), 1.33
(s, 3H), 1.32 (s, 3H), 1.18 (s, 3H), 1.08 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 135.7, 134.7, 112.4, 89.3, 88.3, 81.5,
76.0, 46.1, 45.8, 40.5, 39.8, 39.0, 38.9, 37.2, 26.8, 24.6,
21.1, 21.0, 20.6; IR, nmax 2981, 2937, 1336, 1173, 1059,
933, 881, 860, 527 cm21; MS, m/z (EI, 70 eV) 450 (Mþz,
2%), 435 (6), 421 (7), 392 (10), 200 (100), 185 (34), 171
(52), 158 (44), 100 (54).
3.2.9. (3aR,4S,4aS,7aS,8R,8aS)-3a,4,4a,6,7,7a,8,8a-Octa-
hydro-2,2,4,6,6-pentamethyl-4,8-etheno-5H-indeno[5,6-
d]-1,3-dioxol-5-one (23). A magnetically stirred solution of
3.2.7. (3aR,4S,7R,7aS,8R,9S)-3a,4,7,7a-Tetrahydro-8-
(hydroxymethyl)-2,2,4-trimethyl-6-(2-methyl-1-pro-

542
M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
the ketone 22 (2.77 g, 11.2 mmol) in THF (20 mL)
maintained at 0 8C was treated, dropwise over 5 min., with
LiHMDS (11.7 mL of a 1 M solution in THF, 11.7 mmol).
The resulting mixture was stirred at 0 8C for 0.75 h then
warmed to 18 8C over 1.25 h. The reaction mixture was
re-cooled to 0 8C then treated, dropwise, with MeI
(0.73 mL, 11.73 mmol), allowed to stir for 0.75 h, then
warmed to 18 8C over a period of 1.25 h. The reaction
mixture was then re-cooled to 0 8C and treated with a further
aliquot of LiHMDS (11.7 mL of a 1 M solution in THF,
11.7 mmol) then MeI (0.73 mL, 11.73 mmol) using the
warming and cooling cycle mentioned above. This process
was repeated twice more then the reaction mixture treated,
at 18 8C, with NH4Cl (20 mL of a saturated aqueous
solution) and Na2S2O3 (20 mL of a saturated aqueous
solution). The separated aqueous phase was extracted with
ethyl acetate (4£30 mL) and the combined organic phases
were dried (Na2SO4), filtered and concentrated under
reduced pressure to give a dark-yellow oil containing
small amounts of lithium iodide. This material was
subjected to flash chromatography (silica, 1:4!2:3 v/v
ethyl acetate–hexane gradient elution) and concentration of
the appropriate fractions (Rf 0.8 in 1:1 v/v ethyl acetate–
hexane) afforded the title ketone 23 (3.08 g, 100%) as a
white crystalline solid, mp 70–72 8C, [a]D¼247 (c 0.6,
CHCl3) (Found: Mþz, 276.1724. C, 73.5. H, 8.5. C17H24O3
requires Mþz, 276.1725. C, 73.5. H, 8.5%). 1H NMR
(CDCl3, 300 MHz) d 6.00 (broad t, J¼7.4 Hz, 1H), 5.88 (dd,
J¼8.1, 0.6 Hz, 1H), 4.13 (dd, J¼8.1, 3.9 Hz, 1H), 3.68 (d,
J¼8.4 Hz, 1H), 3.08 (ddd, J¼19.8, 9.3, 2.1 Hz, 1H), 2.88–
2.78 (complex m, 2H), 1.85 (dd, J¼12.9, 9.0 Hz, 1H), 1.55
(s, 3H), 1.50 (s, 3H), 1.34 (s, 3H), 1.25 (dd, J¼12.9, 9.3 Hz,
1H), 1.01 (s, 3H), 0.91 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 223.9, 138.9, 132.0, 112.0, 81.8, 76.0, 47.1, 46.1, 41.6,
40.4, 40.2, 29.6, 26.8, 24.8, 22.5, 19.9 (one signal obscured
or overlapping); IR, nmax 2961, 2933, 2899, 1736, 1381,
1373, 1263, 1207, 1063, 1052, 881, 711 cm21; MS, m/z (EI,
70 eV) 276 (Mþz, 4%), 261 (10), 218 (27), 176 (55), 134
(67), 105 (100), 91 (37), 75 (57).
[a]D¼þ75 (c 0.2, CHCl3) [Found: (M2CH3z)þ,
263.1648.C, 73.0; H, 9.2. C17H26O3 requires (M2CH3z)þ,
263.1647. C, 73.4; H, 9.4%]. 1H NMR (CDCl3, 300 MHz) d
6.14–6.03 (complex m, 2H), 4.09 (dd, J¼8.1, 3.9 Hz, 1H),
3.73 (d, J¼8.1 Hz, 1H), 3.56 (dd, J¼10.5, 6.0 Hz, 1H),
2.93–2.82 (m, 1H), 2.78–2.70 (m, partially obscured, 1H),
2.72 (dd, J¼10.8, 6.0 Hz, 1H), 1.48 (s, 3H), 1.44–1.35 (m,
partially obscured, 1H), 1.37 (s, 3H), 1.34 (s, 3H), 1.12 (d,
J¼10.8 Hz, 1H), 1.08 (t, J¼11.7 Hz, 1H), 0.96 (s, 3H), 0.93
(s, 3H); 13C NMR (CDCl3, 75 MHz) d 141.4, 131.6, 112.1,
83.0, 81.3, 47.1, 43.9, 41.6, 41.0, 39.0, 37.2, 26.8, 26.2,
24.9, 23.0, 20.6 (one signal overlapping or obscured); IR,
n
max 3500, 2935, 1464, 1380, 1371, 1261, 1207, 1081, 1056,
1028, 880 cm21; MS, m/z (EI, 70 eV) 279 [(MþH)þ, 2%],
263 (5), 249 (15), 220 (23), 178 (42), 106 (48), 105 (37), 93
(39), 75 (100).
Concentration of fraction B (Rf 0.4 in 3:7 v/v ethyl acetate–
hexane), afforded the a-epimeric form of the title alcohol
24b (5.54 g, 91%) as a white crystalline solid, mp 88–
89 8C, [a]D¼þ18 (c 0.4, CHCl3) [Found: (M2CH3z)þ,
263.1648. C, 73.4; H, 9.3. C17H26O3 requires (M2CH3z)þ,
263.1647. C, 73.4; H, 9.3%]. 1H NMR (CDCl3, 300 MHz) d
6.10 (broad t, J¼7.2 Hz, 1H), 5.87 (dm, J¼8.1 Hz, 1H), 4.11
(dd, J¼8.1, 3.9 Hz, 1H), 3.77 (d, J¼8.1 Hz, 1H), 3.25 (t,
J¼7.2 Hz, 1H), 2.83–2.72 (m, 1H), 2.67–2.62 (m, 1H),
2.17 (dd, J¼10.5, 9.0 Hz, 1H), 1.51–1.44 (m, partially
obscured, 1H), 1.48 (s, 3H), 1.33 (s, 3H), 1.32 (s, 3H), 1.24
(d, J¼7.2 Hz, 1H), 0.95 (m, partially obscured, 1H), 0.93 (s,
3H), 0.89 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 139.1,
133.5, 111.9, 83.5, 81.2, 76.7, 47.9, 41.9, 41.6, 40.6, 39.7,
33.9, 26.7, 26.6, 24.8, 21.5, 20.6; IR, nmax 3494, 2948, 2930,
1457, 1380, 1371, 1263, 1205, 1064, 1053, 1038, 877, 729,
711 cm21; MS, m/z (EI, 70 eV) 279 [(MþH)þ, 1%], 278
(Mþz, ,1), 263 (1), 220 (23), 187 (26), 178 (100), 106 (61),
105 (43), 91 (35).
3.2.11. (3aR,4S,4aS,7aR,8R,8aS)-3a,4a,5,6,7,7a,8,8a-
Octahydro-2,2,4,6,6-pentamethyl-4,8-etheno-4H-
indeno[5,6-d]-1,3-dioxole (25).
3.2.10. (3aR,4S,4aS,5S,7aS,8R,8aS)-3a,4,4a,6,7,7a,8,8a-
Octahydro-2,2,4,6,6-pentamethyl-4,8-etheno-5H-
indeno[5,6-d]-1,3-dioxol-5-ol (24a) and (3aR,4S,4aS,5-
R,7aS,8R,8aS)-3a,4,4a,6,7,7a,8,8a-octahydro-2,2,4,6,6-
pentamethyl-4,8-etheno-5H-indeno[5,6-d]-1,3-dioxol-5-
ol (24b). A magnetically stirred solution of lithium
aluminium hydride (852 mg, 22.4 mmol) in THF (80 mL)
maintained at 0 8C (ice bath) was treated, dropwise over 4 h,
with a solution of ketone 23 (6.07 g, 22.0 mmol) in THF
(60 mL). After a further 2 h at 0 8C the reaction mixture was
heated at 50 8C for 18 h then cooled to 0 8C and treated with
3.2.11.1. Step (i). THF (10 mL) was cooled to 0 8C and
treated with alcohol 24a (407 mg, 1.46 mmol) and sodium
hydride (298 mg of a 60% dispersion in mineral oil,
7.44 mmol). The resulting mixture was heated at reflux for
6 h then cooled to 18 8C and treated rapidly with carbon
disulfide (880 mL, 14.6 mmol). After 11 h the reaction
mixture was heated at reflux for 2 h then cooled to 18 8C
again and treated with methyl iodide (1.00 mL,
16.08 mmol). After 2 h the reaction mixture was heated at
reflux for 6 h then cooled to 18 8C. The reaction mixture was
then quenched with acetic acid (0.5 mL). The resulting
mixture was filtered through a short pad of Celitew and the
solids thus retained washed with ethyl acetate (4£10 mL).
The combined filtrates were washed with NaHCO3
(2£10 mL of a saturated aqueous solution) then dried
(MgSO4), filtered and concentrated under reduced pressure
to give a yellow oil. Subjection of this material to flash
chromatography (silica, 0:4!1:4 v/v ethyl acetate–hexane
gradient elution) and concentration of the appropriate
fractions (Rf 0.4 in 1:9 v/v ethyl acetate–hexane) afforded
(3aR,4S,4aS,5S,7aS,8R,8aS)-3a,4,4a,6,7,7a,8,8a-octahydro-
2,2,4,6,6-pentamethyl-4,8-etheno-5H-indeno[5,6-d]-1,3-diox-
ol-5-ol S-methyl xanthate (538 mg, 87%) as a clear, colourless
Na2SO4 (3 mL of
a
saturated aqueous solution,
CAUTION!). The resulting grey-white precipitate was
removed by filtration and washed with ethyl acetate
(multiple small washings to a total volume of 250 mL).
The combined filtrate was concentrated under reduced
pressure to give a clear, colourless oil. Subjection of this
material to flash chromatography (silica, 1:4 v/v ethyl
acetate–hexane elution) afforded two fractions, A and B.
Concentration of fraction A (Rf 0.5 in 3:7 v/v ethyl acetate–
hexane), afforded the b-epimeric form of the title alcohol
24a (502 mg, 8%) as a white crystalline solid, mp 61–62 8C,

M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
543
oil, [a]D¼þ19 (c 0.3, CHCl3) (Found: Mþz, 368.1487. C, 61.7;
H, 7.9; S, 17.5. C19H28O3S2 requires Mþz, 368.1480. C, 61.9;
H, 7.7; S, 17.4%). 1H NMR (CDCl3, 300 MHz) d 6.00–5.92
(complex m, 3H), 4.14 (dd, J¼8.1, 3.9 Hz, 1H), 3.72 (d,
J¼8.1 Hz, 1H), 2.95–2.82 (complex m, 2H), 2.81–2.76 (m,
1H), 2.57 (s, 3H), 1.47 (s, 3H), 1.44–1.34 (complex m, 2H),
1.33 (s, 3H), 1.12 (s, 3H), 1.02 (s, 3H), 0.89 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 216.3, 140.6, 128.6, 112.0, 92.9, 81.4,
76.6, 45.9, 45.0, 42.4, 40.9, 38.4, 36.6, 26.8, 25.8, 24.7, 22.8,
20.5, 19.3; IR, nmax 2962, 2932, 1456, 1380, 1369, 1261, 1233,
1224, 1185, 1050, 1029, 879, 713 cm21; MS, m/z (EI, 70 eV)
368 (Mþz, 18%), 353 (12), 261 (54), 203 (95), 185 (50), 160
(42), 95 (100).
44.1, 42.1, 41.0, 39.7, 38.5, 36.7, 29.0, 28.1, 26.7, 24.9,
20.7; IR, nmax 2951, 2934, 1457, 1380, 1370, 1262, 1206,
1064, 1053, 881, 714 cm21; MS, m/z (EI, 70 eV) 247
[(M2CH3z)þ, 10%], 204 (58), 162 (100), 105 (36), 91 (42).
3.2.12. (3aS,4S,7R,7aR,8S,9R)-2,3,3a,4,7,7a-Hexahydro-
2,2,4-trimethyl-4,7-ethano-1H-indene-8,9-diol (26).
A
magnetically stirred solution of acetonide 25 (1.37 g,
5.2 mmol) in acetic acid (20 mL of a 60% v/v solution in
water)–THF (5 mL) was heated at 60 8C for 48 h. The
cooled reaction mixture was treated with NaHCO3 (18 g,
214 mmol) and water (20 mL). After carbon dioxide
evolution had ceased the separated aqueous phase was
extracted with ethyl acetate (5£50 mL) and the combined
organic phases then dried (MgSO4), filtered and concen-
trated under reduced pressure. Subjection of the ensuing
light-yellow oil to flash chromatography (silica,
5:95!30:70 v/v ethyl acetate–hexane gradient elution)
afforded two fractions, A and B.
Reaction of alcohol 24b under the same conditions as
described above for congener 24a afforded a yellow oil on
work-up. Subjection of this material to flash chromato-
graphy (silica, 0:4!1:4 v/v ethyl acetate–hexane gradient
elution) and concentration of the appropriate fractions
(Rf 0.4 in 1:9 v/v ethyl acetate–hexane) afforded
(3aR,4S,4aS,5R,7aS,8R,8aS)-3a,4,4a,6,7,7a,8,8a-octahy-
dro-2,2,4,6,6-pentamethyl-4,8-etheno-5H-indeno-[5,6-d]-
1,3-dioxol-5-ol S-methyl xanthate (100%) as a clear,
colourless oil, [a]D¼þ77 (c 0.2, CHCl3) (Found: Mþz,
368.1484. C, 61.3; H, 7.9; S, 17.3. C19H28O3S2 requires
Mþz, 368.1480. C, 61.9; H, 7.7; S, 17.4%). 1H NMR (CDCl3,
300 MHz) d 6.17 (broad t, J¼7.5 Hz, 1H), 5.94 (d,
J¼7.5 Hz, 1H), 5.66 (d, J¼8.7 Hz, 1H), 4.11 (dd, J¼8.1,
3.9 Hz, 1H), 3.78 (d, J¼8.4 Hz, 1H), 2.97–2.86 (m, 1H),
2.71–2.64 (m, 2H), 2.56 (s, 3H), 1.58–1.52 (m, partially
obscured, 1H), 1.52 (s, 3H), 1.33 (s, 3H), 1.17 (s, 3H), 1.00
(s, 3H), 0.96 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 216.1,
139.1, 133.5, 112.0, 91.9, 81.2, 76.4, 45.2, 42.6, 42.1, 41.2,
39.7, 33.7, 27.0, 26.8, 24.7, 23.0, 20.3, 19.2; IR, nmax 2957,
2932, 1460, 1380, 1370, 1258, 1224, 1206, 1054, 1027, 878,
714 cm21; MS, m/z (EI, 70 eV) 368 (Mþz, ,1%), 353 (11),
260 (71), 231 (35), 203 (72), 202 (62), 187 (65), 160 (71), 95
(100).
Concentration of fraction A (Rf 0.7 in 3:7 v/v ethyl acetate–
hexane) afforded the starting acetonide 25 (772 mg, 56%
recovery) which proved identical, in all respects, with
authentic material.
Concentration of fraction B (Rf 0.3 in 3:7 v/v ethyl acetate–
hexane) afforded a light-yellow solid. Recrystallization
(ethyl acetate) of this material afforded the title diol 26
(483 mg, 95% at 44% conversion) as a white crystalline
solid, mp 91–92 8C, [a]D¼þ56 (c 0.4, CHCl3) [Found:
(M2C2H4O2)þz, 162.1410. C, 75.4; H, 9.8. C14H22O2
requires (M2C2H4O2)þz, 162.1409, C, 75.6; H, 10.0%].
1H NMR (CDCl3, 300 MHz) d 6.06 (broad t, J¼7.8 Hz, 1H),
5.77 (broad d, J¼8.4 Hz, 1H), 3.76–3.70 (m, 1H), 3.34 (dd,
J¼8.7, 5.4 Hz, 1H), 2.97 (d, J¼5.1 Hz, 1H), 2.79 (d,
J¼5.7 Hz, 1H), 2.72–2.57 (complex m, 2H), 2.46–2.36 (m,
1H), 1.45–1.33 (complex m, 2H), 1.14 (s, 3H), 1.05–0.94
(m, partially obscured, 2H), 0.96 (s, 3H), 0.89 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 138.7, 132.5, 70.2, 66.5, 45.6,
44.2, 42.7, 41.9, 40.5, 38.6, 36.1, 29.0, 28.1, 20.4; IR, nmax
3344, 2949, 2930, 1456, 1365, 1053, 1012, 711 cm21; MS,
m/z (EI, 70 eV) 162 [(M2C2H4O2)þz, 100], 147 (40), 106
(35), 91 (33).
3.2.11.2. Step (ii). A magnetically stirred solution of the
relevant xanthate (538 mg, 1.46 mmol), formed as
described above, and AIBN (3.4 mg, 0.02 mmol) in toluene
(20 mL) was treated with tri-n-butyltin hydride (1.20 mL,
4.46 mmol) and the resulting mixture heated at 100 8C for
17 h. The cooled reaction mixture was treated with
additional tri-n-butyltin hydride (0.80 mL, 2.97 mmol) and
AIBN (5.0 mg) and the resulting mixture heated at reflux for
1 h. The cooled reaction mixture was then concentrated
under reduced pressure and the residue subjected to flash
chromatography (silica, 0:100!5:95 v/v ethyl acetate–
hexane gradient elution). Concentration of the relevant
fractions (Rf 0.7 in 3:7 v/v ethyl acetate–hexane) afforded a
solid. Recrystallization (ethyl acetate) of this material
afforded the title acetonide 25 (218 mg, 57%) as a white,
crystalline solid, mp 65–66 8C, [a]D¼þ39 (c 0.4, CHCl3)
[Found: (M2CH3z)þ, 247.1697. C, 77.5; H, 10.0. C17H26O2
3.2.13. (3aS,4S,7R,7aR,9R)-2,3,3a,4,7,7a-Hexahydro-9-
hydroxy-2,2,4-trimethyl-4,7-ethano-1H-indene-8-one
(27). A magnetically stirred suspension of diol 26 (457 mg,
2.06 mmol) and p-TsOH·H2O (822 mg, 4.32 mmol) in
dichloromethane (40 mL) was cooled to 0 8C and 4-aceta-
mido-TEMPO (922 mg, 4.32 mmol) was added in portions
over 1 h. The resulting pale-orange mixture was stirred at
0 8C for 6 h then warmed to 18 8C and stirred at this
temperature for 16 h. After this time the reaction mixture
was treated with NaHCO3 (20 mL of a saturated aqueous
solution) and extracted with dichloromethane (4£20 mL).
The combined organic phases were dried (MgSO4), filtered
and concentrated under reduced pressure. Subjection of the
ensuing orange oil to flash chromatography (silica, 0:1!4:6
v/v ethyl acetate–hexane gradient elution) afforded two
fractions, A and B.
1
requires (M2CH3z)þ, 247.1698. C, 77.8; H, 10.0%]. H
NMR (CDCl3, 300 MHz) d 6.07 (broad t, J¼7.2 Hz, 1H),
5.79 (dt, J¼8.4, 0.9 Hz, 1H), 4.13 (dd, J¼8.4, 3.9 Hz, 1H),
3.79 (d, J¼8.4 Hz, 1H), 2.85–2.66 (complex m, 2H), 2.57–
2.48 (m, 1H), 1.50 (s, 3H), 1.44–1.32 (complex m, partially
obscured, 2H), 1.34 (s, 3H), 1.15 (s, 3H), 1.01–0.93 (m,
partially obscured, 2H), 0.96 (s, 3H), 0.91 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 139.0, 132.9, 111.8, 81.0, 76.9, 45.3,
Concentration of fraction A (Rf 0.4 in 3:7 v/v ethyl acetate–
hexane) afforded the title acyloin 27 (395 mg, 91% at 96%

544
M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
conversion) as a clear, colourless oil, [a]D¼234 (c 0.4,
CHCl3) (Mþz, 220.1464. C, 76.1; H, 9.0. C14H20O2 requires
Mþz, 220.1463. C, 76.3; H, 9.2%). 1H NMR (CDCl3,
300 MHz) d 6.14–6.05 (complex m, 1H), 3.39 (d,
J¼1.8 Hz, 1H), 3.10–3.07 (m, 1H), 2.70–2.50 (complex
m, 3H), 1.68–1.67 (broad m, 1H), 1.54–1.45 (complex m,
2H), 1.25 (s, 3H), 1.17 (dd, J¼11.7, 9.9 Hz, 1H), 1.10 (dd,
J¼12.6, 10.5 Hz, 1H), 0.99 (s, 3H), 0.90 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 213.7, 140.3, 127.8, 74.7, 51.3, 45.9,
45.5, 44.8, 44.2, 41.3, 39.9, 28.8, 27.9, 19.1; IR, nmax 3442,
2952, 2931, 1734, 1722, 1456, 1366, 1074, 788, 767,
707 cm21; MS, m/z (EI, 70 eV) 220 (Mþz, 100%), 205 (43),
163 (64), 161 (70), 105 (47), 91 (61).
gradient elution) and thereby yielding two major fractions,
A and B.
Concentration of fraction A (Rf 0.2 in 3:7 v/v ethyl acetate–
hexane) afforded a white crystalline solid which was
recrystallized (ethyl acetate) thus affording cyclopropane
29 (145 mg, 80% at 71% conversion) as a white crystalline
solid, mp 78–79 8C, [a]D¼þ102 (c 0.2, CHCl3) (Found:
Mþz, 308.1988. C, 70.1; H, 8.9. C18H28O4 requires Mþz,
308.1988. C, 70.1; H, 9.2%). 1H NMR (CDCl3, 300 MHz) d
4.99 (d, J¼6.9 Hz, 1H), 4.81 (d, J¼6.9 Hz, 1H), 3.88-3.74
(complex m, 3H), 3.58-3.55 (m, 2H), 3.39 (s, 3H), 2.68 (dt,
J¼12.0 and 7.0 Hz, 1H), 2.38-2.31 (m, 1H), 2.10 (t,
J¼5.4 Hz, 1H), 1.90-1.78 (complex m, 3H), 1.64 (dd,
J¼10.3, 5.6 Hz, 1H), 1.45 (t, J¼11.9 Hz, 1H), 1.36-1.22
(complex m, partially obscured, 1H), 1.34 (s, 3H), 1.08 (s,
3H), 0.86 (s, 3H); 13C NMR (75 MHz, CDCl3) d 210.8,
95.6, 88.1, 72.0, 67.5, 59.4, 53.4, 49.9, 48.9, 43.5, 43.3,
40.8, 36.0, 33.7, 32.1, 29.8, 27.7, 21.4; IR, nmax 2971, 2956,
2933, 2869, 1731, 1110, 1055, 1010 cm21; MS, (EI, 70eV)
m/z 308 (Mþz, 2%), 279 (9), 219 (53), 108 (70), 89 (88), 59
(100).
Concentration of fraction B (Rf 0.3 in 3:7 v/v ethyl acetate–
hexane) afforded the starting diol 26 (18 mg, 4% recovery)
which was identical, in all respects, with authentic material.
3.2.14. (3aS,4S,7R,7aR,9R)-2,3,4,4a,7,7a-Hexahydro-9-
[(2-methoxyethoxy)methoxy]-2,2,4-trimethyl-4,7-
ethano-1H-indene-8-one (28). A solution of acyloin 27
(347 mg, 1.57 mmol) and Hu¨nig’s base (690 mL,
3.96 mmol) in dichloromethane (3.5 mL) maintained at
18 8C was treated in a dropwise fashion with MEM-Cl
(360 mL, 3.15 mmol) and the resulting mixture stirred at
18 8C for 16 h then treated with NaHCO3 (2 mL of a
saturated aqueous solution). The separated aqueous phase
was extracted with dichloromethane (5£10 mL) and the
combined organic phases then washed with water
(1£50 mL), dried (Na2SO4), filtered and concentrated
under reduced pressure. Subjection of the ensuing light-
brown oil to flash chromatography (silica, 0:99:1!20:79:1
v/v/v ethyl acetate–hexane–triethylamine gradient elution)
afforded, after concentration of the appropriate fractions (Rf
0.4 in 3:7 v/v ethyl acetate–hexane), the title ether 28
(444 mg, 91%) as a clear, colourless oil, [a]D¼þ28 (c 0.4,
CHCl3) (Found: Mþz, 308.1986. C, 69.8; H, 8.8. C18H28O4
requires Mþz, 308.1988. C, 70.1; H, 9.2%). 1H NMR
(CDCl3, 300 MHz) d 6.10 (dd, J¼8.4, 6.0 Hz, 1H), 6.03
(broad d, J¼8.1 Hz, 1H), 5.11 (d, J¼6.8 Hz, 1H), 4.81 (d,
J¼6.8 Hz, 1H), 3.88–3.75 (m, 2H), 3.59–3.56 (m, 2H),
3.46 (s, 1H), 3.39 (s, 3H), 2.98 (dm, J¼6 Hz, 1H), 2.71–
2.58 (m, 2H), 1.54–1.43 (m, 2H), 1.21 (s, 3H), 1.16–1.08
(m, 1H), 1.04–0.97 (m, partially obscured, 1H), 0.99 (s,
3H), 0.91 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 210.0,
140.1, 128.4, 96.4, 76.9, 72.0, 67.7, 59.4, 52.5, 45.5, 44.9,
44.2, 43.4, 42.1, 39.6, 28.8, 27.9, 19.6; IR, nmax 2951, 2931,
1736, 1457, 1366, 1110, 1036, 708 cm21; MS, m/z (EI,
70 eV) 308 (Mþz, 6%), 279 (5), 175 (47), 108 (50), 89 (100),
59 (93).
Concentration of fraction B (Rf 0.4 in 3:7 v/v ethyl acetate–
hexane) afforded the starting ether 28 (73 mg, 29%
recovery) which proved identical, in all respects, with
authentic material.
3.2.16. (3R,3aS,3bS,6aR,7aR)-Decahydro-3-[(2-methoxy-
ethoxy)methoxy]-3a,5,5-trimethyl-2H-cyclopenta[a]pen-
talen-2-one (30). A magnetically stirred solution of
compound 29 (145 mg, 0.47 mmol) and AIBN (3.4 mg,
0.021 mmol) in benzene (15 mL) maintained at 18 8C was
treated, dropwise, with tri-n-butyltin hydride (254 mL,
0.94 mmol) and the resulting mixture allowed to stand for
1 h, then heated at reflux for the same period. The cooled
reaction mixture was treated with further aliquots of AIBN
(5.9 mg, 0.036 mmol) and tri-n-butyltin hydride, then
heated at reflux for a further 2 h. This process was repeated
twice more and such that the total heating time was 8 h. The
cooled reaction mixture was then concentrated under
reduced pressure and the ensuing light-yellow oil subject
to flash chromatography (silica, 0:1!3:7 v/v ethyl acetate–
hexane elution) thus affording two fractions, A and B.
Concentration of fraction A (Rf 0.3 in 3:7 v/v ethyl acetate–
hexane) afforded the title triquinane 30 (104 mg, 87% at
81% conversion) as a clear, colourless oil, [a]D¼þ20 (c 0.4,
CHCl3) (Found: Mþz, 310.2141. C, 69.6; H, 9.7. C18H30O4
requires Mþz, 310.2144. C, 69.6; H, 9.7). 1H NMR (CDCl3,
300 MHz) d 4.95 (d, J¼6.9 Hz, 1H), 4.80 (d, J¼6.9 Hz,
1H), 4.05 (d, J¼1.8 Hz, 1H), 3.80–3.76 (m, 2H), 3.57–3.53
(m, 2H), 3.38 (s, 3H), 2.78–2.62 (m, 1H), 2.54–2.37
(complex m, 3H), 1.88 (dd, J¼17.7, 5.4 Hz, 1H), 1.78–1.70
(m, partially obscured, 2H), 1.66–1.50 (complex m, 1H),
1.40–1.24 (complex m, 2H), 1.16 (s, 3H), 1.07–1.00
(m, partially obscured, 1H), 1.04 (s, 3H), 0.90 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 216.6, 95.6, 88.4, 72.0, 67.3,
59.3, 50.6, 49.2, 47.1, 46.6, 44.8, 43.9, 42.2, 39.4, 37.1,
29.6, 27.4, 22.9; IR, nmax 2949, 2867, 1752, 1466, 1134,
1111, 1098, 1044 cm21; MS, m/z (EI, 70 eV) 310 (Mþz,
1%), 221 (35), 161 (35), 149 (25), 109 (29), 96 (80), 89 (84),
59 (100).
3.2.15. (1R,2aS,2bS,2cS,5aS,5bR,5cR)-Decahydro-1-[(2-
methoxyethoxy)methoxy]-4,4,5d-trimethyl-2H-cyclo-
penta[a]cyclopropa[cd]pentalen-2-one (29). A deoxyge-
nated solution of compound 28 (254 mg, 0.82 mmol) and
acetophenone (240 mL, 2.06 mmol) in acetone (120 mL)
and contained in a Pyrexe vessel jacketed by a water-
cooled solution of sodium bromide (750 g) and lead(II)
nitrate (8 g) in water (1 L) was subject to irradiation from
a Philips 125 W HPL-N lamp for 32 h. The reaction
mixture was then concentrated under reduced pressure
and the resulting clear, colourless oil subject to flash
chromatography (silica, 0:1!3:7 v/v ethyl acetate–hexane

M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
545
Concentration of fraction B (Rf 0.2 in 3:7 v/v ethyl acetate–
hexane) afforded the starting cyclopropane 29 (27 mg, 19%
recovery) which was identical, in all respects, with authentic
material.
was converted into compound 31 (92%) which was obtained
as a clear, colourless oil, [a]D¼þ32 (c 0.4, CHCl3) (Found:
Mþz, 296.2337. C, 72.8; H, 11.3. C18H32O3 requires Mþz,
1
296.2351. C, 72.9; 10.9%). H NMR (CDCl3, 300 MHz) d
4.75 (d, J¼6.9 Hz, 1H), 4.70 (d, J¼6.9 Hz, 1H), 3.72–3.65
(complex m, 3H), 3.57–3.54 (complex m, 2H), 3.40 (s, 3H),
2.69 (q, J¼9.6 Hz, 1H), 2.62–2.48 (m, 1H), 2.07–2.00 (m,
1H), 1.98–1.86 (m, 1H), 1.76–1.56 (complex m, 4H),
1.49–1.25 (complex m, 4H), 1.10–1.03 (m, partially
obscured, 1H), 1.05 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H);
13C NMR (CDCl3, 75 MHz) d 95.3, 88.1, 72.1, 66.9, 59.3,
54.2, 51.7, 48.5, 47.9, 44.8, 43.5, 42.5, 40.9, 31.2, 30.5, 28.5,
28.3, 23.8; IR, nmax 2949, 2869, 1464, 1364, 1136, 1111,
1045 cm21; MS, m/z (EI, 70 eV) 296 (Mþz, ,1%), 220 (60),
207 (50), 190 (44), 189 (49), 163 (37), 107 (46), 89 (100).
3.2.17. (3aS,3bS,4S,6aS,7aR)-Decahydro-4-[(2-methoxy-
ethoxy)methoxy]-2,2,3b-trimethyl-1H-cyclopenta[a]pen-
talene (31)
3.2.17.1. Step (i). A magnetically stirred solution of
ketone 30 (100 mg, 0.33 mmol) in methanol (15 mL)
maintained at 18 8C was treated with NaBH4 (28 mg,
0.73 mmol). After 4 h the reaction mixture was diluted with
ethyl acetate (2 mL) then treated with water (15 mL). The
separated aqueous phase was extracted with ethyl acetate
(5£15 mL) and the combined organic phases were then
dried (Na2SO4), filtered and concentrated under reduced
pressure. Subjection of the ensuing clear, colourless oil to
flash chromatography (silica, 1:9 v/v ethyl acetate-hexane
elution) afforded, after concentration of the appropriate
fractions (Rf 0.2 in 3:7 v/v ethyl acetate–hexane),
(2S,3R,3aS,3bS,6aR,7aR)-decahydro-3-[(2-methoxyethoxy)-
methoxy]-3a,5,5-trimethyl-2H-cyclopenta[a]pentalen-2-ol
(99.6 mg, 98%) as a clear, colourless oil, [a]D¼þ12 (c 0.6,
CHCl3) (Found: Mþz, 312.2298. C, 69.0; H, 10.1. C18H32O4
requires Mþz, 312.2301 C, 69.2; 10.3%). 1H NMR (CDCl3,
300 MHz) d 4.87 (d, J¼6.9 Hz, 1H), 4.77 (d, J¼6.9 Hz,
1H), 4.16–4.08 (m, 1H), 3.88–3.81 (complex m, 1H),
3.78–3.71 (complex m, 1H), 3.59–3.52 (complex m, 3H),
3.40 (s, 3H), 3.01 (d, J¼5.7 Hz, 1H), 2.82–2.66 (complex
m, 2H), 2.18–2.08 (m, 1H), 2.01–1.92 (m, 1H), 1.69–1.58
(m, partially obscured, 1H), 1.52–1.04 (complex m,
partially obscured, 6H), 1.06 (s, 3H), 1.01 (s, 3H), 0.94 (s,
3H); 13C NMR (CDCl3, 75 MHz) d 97.4, 91.3, 72.9, 72.0,
68.1, 59.4, 53.4, 50.0, 48.4, 47.7, 44.3, 42.8, 42.3, 39.9,
39.2, 30.9, 29.1, 24.9; IR, nmax 3479, 2930, 2865, 1462,
1364, 1170, 1097, 1036, 849 cm21; MS, m/z (EI, 70 eV) 313
[(MþH)þ, 1%], 312 (Mþz, ,1), 236 (24), 206 (22), 179
(39), 161 (55), 149 (53), 89 (78), 59 (100).
3.2.17.2. Step (ii). Following the same protocol as
employed for the conversion of compound 24 into the
corresponding xanthate ester, the abovementioned alcohol
was converted into (2S,3R,3aS,3bS,6aR,7aR)-decahydro-3-
[(2-methoxyethoxy)methoxy]-3a,5,5-trimethyl-2H-cyclo-
penta[a]pentalen-2-ol S-methyl xanthate (92%) which was
obtained as a clear, colourless oil, [a]D¼þ45 (c 0.4, CHCl3)
[Found: (M2HSz)þ, 369.2100. C, 59.8; H, 8.7; S, 15.6.
C20H34O4S2 requires (M2HSz)þ, 369.2100. C, 59.7; 8.5; S,
15.9%]. 1H NMR (CDCl3, 300 MHz) d 5.87–5.82 (m, 1H),
4.73 (dd, J¼11.4, 6.9 Hz, 2H), 3.83 (d, J¼5.1 Hz, 1H),
3.80–3.65 (complex m, 2H), 3.53 (t, J¼5.1 Hz, 2H), 3.37 (s,
3H), 3.01–2.91 (m, 1H), 2.79–2.65 (m, 1H), 2.56 (s, 3H),
2.38–2.28 (m, 1H), 2.09–2.02 (m, 1H), 1.72–1.58 (com-
plex m, 3H), 1.55–1.45 (m, 1H), 1.37–1.25 (m, 2H), 1.15–
1.10 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 215.4, 96.2, 86.7, 84.3, 72.0,
67.6, 59.3, 53.4, 49.7, 47.7, 44.2, 43.0, 42.8, 40.4, 36.0,
30.6, 28.7, 24.5, 19.3 (one signal obscured or overlapping);
IR, nmax 2929, 1730, 1464, 1220, 1062 cm21; MS, m/z (EI,
70 eV) 369 [(M2HSz)þ, 7%], 355 (5), 190 (8), 149 (12),
105 (10), 89 (100), 59 (95).
3.2.18. (3S,3aS,3bS,6aR,7aS)-Decahydro-3a,5,5-tri-
methyl-1H-cyclopenta[a]pentalen-3-ol (32). A magneti-
cally stirred solution of the MEM-ether 31 (9.5 mg,
0.032 mmol) and PPTS (17 mg, 0.068 mmol) in t-butanol
(2 mL) was heated at reflux for 4 h. TLC analysis after this
time indicated that starting material remained so additional
PPTS (4.1 mg, 0.016 mmol) was added and the reaction
mixture heated at reflux for a further 4 h. The cooled
reaction mixture was then concentrated under reduced
pressure. Subjection of the ensuing light-brown oil to flash
chromatography (silica, 0:1!1:4 v/v ethyl acetate–hexane
elution) afforded, after concentration of the appropriate
fractions (Rf 0.2 in 1:9 v/v ethyl acetate–hexane), the title
alcohol 32 (5.1 mg, 76%) as a white, crystalline solid, mp
44–46 8C, [a]D¼þ36 (c 0.1, CHCl3) (Found: Mþz,
208.1830. C, 80.7; H, 11.4. C14H24O requires Mþz,
208.1827. C, 80.7; H, 11.6%). 1H NMR (CDCl3,
300 MHz) d 3.78 (t, J¼6.6 Hz, 1H), 2.66–2.51 (complex
m, 2H), 2.12–2.04 (m, 1H), 2.01–1.91 (complex m, 1H),
1.80–1.25 (complex m, 9H), 1.12–1.05 (m, partially
obscured, 1H), 1.06 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H);
13C NMR (CDCl3, 75 MHz) d 83.2, 55.0, 51.7, 48.5, 47.6,
44.9, 43.6, 42.5, 40.9, 33.8, 30.4, 28.3, 28.2, 23.3; IR, nmax
3376, 2949, 2932, 2864, 1464, 1364, 1075 cm21; MS, m/z
(EI, 70 eV) 208 (Mþz, 50%), 190 (14), 149 (100), 123 (30),
107 (54), 93 (38).
3.2.19. (3aS,3bS,6aR,7aS)-Decahydro-3a,5,5-trimethyl-
3H-cyclopenta[a]pentalen-3-one (33). A magnetically
stirred solution of alcohol 32 (33.2 mg, 0.159 mmol) in
dichloromethane (10 mL) was treated with PCC (68.7 mg,
0.32 mmol). The resulting orange-yellow mixture was
stirred at 18 8C for 16 h by which time it had turned red-
brown in color. The solvent was removed under a stream of
nitrogen and the residue subject to flash chromatography
(silica, 5:95 v/v ethyl acetate–pentane elution). Concen-
tration of the appropriate fractions (Rf 0.5) afforded the title
ketone 337 (23 mg, 71%) as a white crystalline solid, mp
23–24 8C, [a]D¼256 (c 0.4, CHCl3) (Found: Mþz,
206.1671. C, 81.7; H, 11.1. C14H22O requires Mþz,
206.1671. C, 81.5; H, 10.8%). 1H NMR (CDCl3,
300 MHz) d 2.84–2.75 (m, 1H), 2.58–2.45 (m, 1H),
2.44–2.21 (complex m, 3H), 2.06–1.93 (complex m, 1H),
1.77–1.55 (complex m, 3H), 1.48–1.34 (complex m, 2H),
1.17 (t, J¼11.1 Hz, 1H), 1.04 (s, 3H), 1.04–0.94 (m,
partially obscured, 1H), 0.94 (s, 3H), 0.90 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 224.8, 59.7, 49.2 (0), 49.1 (8), 47.0,
3.2.17.3. Step (iii). Following the same protocol as
employed for the conversion of compound 24 into the
corresponding hydrocarbon, the abovementioned xanthate

546
M. G. Banwell et al. / Tetrahedron 60 (2004) 535–547
43.7, 42.2, 41.5, 37.9, 34.6, 29.6, 26.9, 22.7, 17.7; IR, nmax
2933, 2866, 1739, 1464, 1365, 1008 cm21; MS, m/z (EI,
70 eV) 206 (Mþz, 100%), 191 (10), 162 (46), 150 (39), 149
(36), 107 (56).
Acknowledgements
Dr. Gregg Whited and Professor Tomas Hudlicky are
warmly thanked for providing generous quantities of the
diol 2. G. J. H. is the grateful recipient of an ANU Graduate
School PhD Scholarship. We thank the Institute of
Advanced Studies (IAS) for financial support including
the provision of an IAS post-Doctoral Fellowship to K. A. J.
Drs. Ken McRae and Scott Stewart are thanked for carrying
out some preliminary experiments.
3.2.20. (3aS,3bS,6aS,7aR)-Decahydro-2,2,3b-trimethyl-
4-methylene-1H-cyclopenta[a]pentalene [(2)-hirsutene,
(2)-1]. A magnetically stirred solution of methyl tri-
phenylphosphonium bromide (68.9 mg, 0.19 mmol) in
freshly distilled toluene (10 mL) maintained at 0 8C was
treated, dropwise, with KHMDS (297 mL of a 15% w/v
solution in toluene, 0.197 mmol). The resulting intensely
yellow-colored solution was stirred at 0 8C for 1 h then
brought to 18 8C over 1 h and immediately re-cooled to
0 8C. A degassed solution of ketone 33 (19.8 mg,
0.096 mmol) in toluene (5 mL) was added, dropwise, to
the reaction mixture which was then heated at reflux for
1.5 h. The solvent was removed from the cooled reaction
mixture under a stream of nitrogen. Subjection of the
ensuing light-yellow oil to flash chromatography (silica,
pentane elution) afforded two fractions, A and B.
References and notes
1. For reviews on polyquinanes, including triquinanes, see:
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Concentration of fraction A (Rf 0.6) afforded (2)-hirsutene
(2)-1] (6.3 mg, 100% at 32% conversion) as a clear,
colourless oil, [a]D¼226 (c 0.2, CDCl3) (Found: Mþz,
204.1876. C15H24 requires Mþz, 204.1878). 1H NMR
(CDCl3, 600 MHz) d 4.83–4.81 (m, 1H), 4.78–4.76 (m,
1H), 2.63–2.58 (m, 1H), 2.53–2.47 (m, 1H), 2.48–2.44
(complex m, 2H), 2.17–2.13 (m, 1H), 1.76–1.70 (m, 1H),
1.63 (ddd, J¼10.2, 8.4, 1.8 Hz, 1H), 1.48–1.43 (m, 1H),
1.43–1.40 (m, 2H), 1.25 (broad s, 1H), 1.20 (t, J¼11.4 Hz,
1H), 1.05 (s, 3H), 1.02 (dd, J¼12.6, 7.8 Hz, 1H), 0.94 (s,
3H), 0.91 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 163.0,
103.8, 56.3, 53.8, 50.3, 49.3, 44.6, 42.2, 41.3, 39.0, 31.3,
30.1, 27.6, 27.2, 23.6; IR, nmax 2931, 2865, 1649, 1464,
1364, 876 cm21; MS, m/z (EI, 70 eV) 204 (Mþz, 9%), 189
(3), 94 (100), 79 (34).
3. Schuda, P. F.; Phillips, J. L.; Morgan, T. M. J. Org. Chem.
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3.3. Crystallographic studies
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3.3.1. Crystal data for 11. C17H26O4, M¼294.391,
T¼200(1) K, monoclinic, space group P21, Z¼2, a¼
9. Banwell, M. G.; Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.
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˚
9.2853(2), b¼8.2538(2), c¼10.7776(3) A, b¼107.9399(10)8,
3
V¼785.83(3) A , Dx¼1.244 Mgm23, 1926 unique data
˚
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(2Qmax¼55.068), 1608 with I$3.00s(I); R¼0.032,
Rw¼0.030, S¼1.074.
Images were measured on a Nonius Kappa CCD diffract-
˚
ometer (Mo Ka, graphite monochromator, l¼0.71073 A)
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the Cambridge Crystallographic Data Centre as supplemen-
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can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax:þ44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
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dissymmetric dienes see (a) Mehta, G.; Uma, R. Acc. Chem.

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