Synthesis of a caryophyllene isoprenologue, a potential diterpene natural product

Article abstract of DOI:10.1016/j.tet.2005.02.018

(-)-β-Caryophyllene has been converted into three stereoisomers of a new bicyclic compound that is structurally related to the known macrocyclic diterpene, flexibilene, in the same way β-caryophyllene is related to humulene. Key steps are selective cleava

Full text of DOI:10.1016/j.tet.2005.02.018

Tetrahedron 61 (2005) 3671–3680
Synthesis of a caryophyllene isoprenologue, a potential diterpene
natural product
Simon F. R. Hinkley,a Nigel B. Perryb and Rex T. Weaversa,
*
aDepartment of Chemistry, University of Otago, Box 56, Dunedin, New Zealand
bPlant Extracts Research Unit, Crop and Food Research, Department of Chemistry, University of Otago, Dunedin, New Zealand
Received 21 October 2004; revised 24 January 2005; accepted 10 February 2005
Abstract—(K)-b-Caryophyllene has been converted into three stereoisomers of a new bicyclic compound that is structurally related to the
known macrocyclic diterpene, flexibilene, in the same way b-caryophyllene is related to humulene. Key steps are selective cleavage of
caryophyllene, addition of a five carbon component by a Wittig reaction and McMurry cyclization.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
proceeds through an intermediate with a caryophyllene
framework.4 For this reason we became interested in
compound 4 which bears the same relationship to
flexibilene (2) as caryophyllene (5) does to humulene (6).
Although 4 has not been encountered as a natural
product, this relationship to flexibilene renders it a
worthwhile synthetic target and the putative connection to
laurenene adds further impetus to its synthesis. Here we
describe our synthesis of 4 and two of its geometric isomers
7 and 8.
During our studies of the tetracyclic diterpene, laurenene
(1)1,2 we have been drawn to the similarity of its
peripheral methylation pattern with that of the
monocyclic diterpene, flexibilene (2).3 We have also
noted structural similarities to the triquinane sesquiterpenes,
and have entertained the idea that the biosynthesis of
laurenene might involve a pathway analogous to that
proposed for the biosynthesis of silphenene (3) which
2. Results and discussion
Keywords: Bicyclic diterpene; Flexibilene; Wittig reaction; Warren
modification; McMurry cyclization.
The readily available (K)-b-caryophyllene (5) presented
itself as an ideal starting point for our synthesis. The
*
Corresponding author. Tel.: C64 3 479 7925; fax: C64 3 479 7906;
e-mail: rweavers@alkali.otago.ac.nz
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.018

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Scheme 1. Selective cleavage of (K)-b-caryophyllene 5. (a) O3/MeOH then (CH3)2S; (b) O3/MeOH then (CH3)2S/K-10 clay/MeOH; (c) HO(CH2)3OH/HC
.
Scheme 2. Synthesis of five carbon subunits 12 and 13. (a) AlCl3/NaI; (b) COCl2/DMSO; (c) Ph3P; (d) (CH2OH)2/PTSA; (e) NaOH.
gem-dimethyl substituted cyclobutane, with a trans fused
ring junction and the exocyclic double bond are already in
place. Transformation of diene 5 into triene 4 requires
enlargement of the nine-membered ring by insertion of an
appropriately functionalized five-carbon unit, to produce the
desired 13-membered ring.
gem-dimethylcyclobutane system, the exocyclic methylene
and the methoxy groups were well resolved, and relatively
unchanged in chemical shift compared with those of the
starting material. Peaks consistent with the dioxolane-
protected methyl ketone system [dH 1.32 (s), 3.93 (m,
Wh/2Z7 Hz); dC 23.5 (q), 109.9 (s), 110.0 (s)] indicated that
the five-carbon unit had been incorporated as desired.
Furthermore, trisubstituted double bond formation was
evidenced by olefinic methine [dH 5.03–5.15 (m); dC
123.8 (d), 124.1 (d)] and methyl peaks [dH 1.67 (d, JZ
1 Hz), 1.59 (s); dC 23.9 (q), 15.9 (q)]. The number of signals
observed in these spectra confirmed the formation of both
the (E)- and the (Z)-forms of alkene 14. Comparison with
literature data13,14 indicated that the (Z)-form [dH 1.67 (d,
JZ1 Hz), dC 23.9 (q)] was dominant and GC indicated a
ratio of 5:11. Other Wittig modifications gave lower yields.
Odinokov et al. have reported the selective ozonolysis of
b-caryophyllene (5) at the endocyclic double bond.5 This
gave ketoaldehyde 9 which was converted into its dimethyl
acetal 10. We found it most convenient to form 10 directly
by carrying out the ozonolysis in methanol and treating the
resulting solution with both dimethyl sulfide and K-10 clay
(Scheme 1). Alternative protection for the aldehyde function
was obtained by treatment of 9 with 1,3-propanediol and
p-toluenesulfonic acid in boiling benzene under Dean–Stark
conditions to give acetal 11.
Attempts to separate the isomers of 14 were only partially
successful. Silica gel radial chromatography provided an
enrichment of the major isomer by repeated elution, but
neither silver nitrate impregnated plates nor reverse phase
C18 column chromatography proved effective. An attempt to
improve the (E)/(Z) ratio of the geometric isomers of 14 by
Conversion of 9 or an equivalent into 4 required the addition
of a 1,4-difunctionalised pentane unit with the attachment of
the 1-position to the ketone function of 9 and the 4-position
to the aldehyde. We chose to commence with functionaliza-
tion of the ketone. Literature methods, involving ring
opening of 2-methyltetrahydrofuran with aluminium tri-
chloride/sodium iodide,6 Swern oxidation7,8 to 5-iodo-2-
pentanone9 and reaction with triphenylphosphine and
acetal-protection, yielded the desired phosphonium salt
12.10,11 Treatment of 12 with boiling aqueous sodium
hydroxide solution gave an alternative five-carbon source,
the diphenylphosphinoyl derivative 1312 (Scheme 2).
Wittig reaction of phosphonium salt 12 with ketoacetal 10
using n-butyl lithium as base in THF gave a 69% yield of an
(E)/(Z) mixture of alkenes 14 (1:2.4 by GC) (Scheme 3).
Although the MS of the product, which was isolated in 65%
yield, showed no parent ion for C24H42O2, peaks for ions
corresponding to loss of CH3, CH3OH, and CH3CH2OH
1
were noted. H and 13C NMR signals associated with the
Scheme 3. Wittig reaction of keto acetal 10.

S. F. R. Hinkley et al. / Tetrahedron 61 (2005) 3671–3680
3673
irradiation in the presence of diphenyldisulphide15,16 gave
very little change in the isomer distribution. In similar
fashion, Wittig reaction of ketone 11 gave the previously
unreported 15 as an (E)/(Z) mixture (40%).
Although the anticipated phosphinoyl alcohols 16 should
exist in four diastereoisomeric forms we did not separate
these. Reaction of the mixed isomers of 16 in dimethyl
formamide with sodium hydride generated the desired
alkenes 14, but only in 30% yield based on transformed
starting material. A promising aspect of this reaction was
that more of the (E)-isomer was formed with a 1:1 ratio of
isomers. This was useful in later studies of the McMurry
cyclisation (vide infra). However, a considerable amount of
keto acetal 10 (35% based on transformed starting material)
was also formed. It was noted that a bright red colour was
formed upon addition of sodium hydride to the diphenyl-
phosphinoyl alcohol. This suggested that fragmentation
may be occurring.
In an attempt to avoid isomeric mixtures, the Warren
modification of the Wittig reaction12,17,18 was attempted.
Here the diastereoisomeric mixtures of phosphinoyl
alcohols that are generated are frequently separable
and able to be transformed stereospecifically into either
the (E)- or (Z)-alkene. Reaction of diphenylphosphinoyl
derivative 13 with ketone 10 gave a solid. The IR spectrum
The same sequence was repeated with the alternative
substrate 11. A low yield (15%) of phosphinoyl alcohol
diastereoisomers 17 was again obtained, but these were
separable by centrifugal chromatography into two fractions
of different Rf on silica. By analogy with Warren’s findings
on similar systems17 it was anticipated that the two isolated
components would correspond to the erythro and threo
forms about the newly created bond. However, when either
of these fractions was treated with sodium hydride in
dimethyl formamide, a 6:5 mixture of alkene 15 (E) and (Z)-
geometric isomers was obtained. Again, a bright red colour
was generated. Lawrence19 has noted that such loss of
stereoselectivity may occur if the alkene is sterically
compressed (tri- or tetra-substituted).
of the mixture indicated that an alcohol (nmax 3350 cmK1
)
was present, and a distinctive band at 1460 cmK1 was
consistent with the diphenylphosphinoyl group. NMR
spectra were complicated, but various resonances supported
the expected gross structure 16. Signals for the geminal
methyl groups (dH 0.84, 0.88), the exocyclic C]CH2 unit
(dH 4.52–5.00, 2H, m; dC 106.5, 106.6, 106.7, 106.8, 151.8
and 152.0), the dioxolane grouping (dH 3.59–4.28, 4H, m;
dC 64.2, 64.4 and 67.7), the methoxy groups (dH 3.31, 6H, s;
dC 52.6) and the phenyl groups (dH 7.48, 6H, m and 7.79,
4H) were noted. Comparison with reported 1H NMR data12
enabled the assignment of a two proton multiplet at
2.32 ppm to both the phosphorus-bearing methine and one
of the ring-junction methine groups. A group of singlets at d
0.96, 0.98 and 1.04 was assigned to the CH3–COH system
and a pair of peaks at 1.24 and 1.27 ppm was assigned to the
methyl group attached to the dioxolane ring (Scheme 4).
Scheme 4. Warren modification of the Wittig reaction of 10. (a) BuLi/THF; (b) NaH/DMF.

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S. F. R. Hinkley et al. / Tetrahedron 61 (2005) 3671–3680
Scheme 5. Synthesis of trienes 4, 7 and 8. (a) HCl(aq)/THF; (b) Ti(0)/DME.
Removal of the acetal functions of 14 by acid hydrolysis
proceeded efficiently, yielding inseparable (E) and (Z)
isomers of product 18 (Scheme 5). Regeneration of the
carbonyl groups was shown by the IR (nmax 2725 (HC]O),
1714 (C]O) cmK1) and NMR spectra (dH 2.13, 3H, s and
9.77, 1H, t, JZ2 Hz; dC 202.3, 208.8). The olefinic methyl
groups of the two isomers gave rise to 1H NMR signals at dH
1.59 and 1.66 for the (E) and (Z) alkenes respectively.
Isomeric ratios of isomers determined by integration of
these signals concurred with those determined by gas
chromatography, and (E)/(Z) mixtures of both 1:1 (from 14
formed by Warren reaction of 10 and 13) and 5:11 (from
Wittig reaction of 10 and 12) were prepared.
With the notable exception of the keto-ester cyclization that
enabled formation of the cyclononene ring in an attempted
synthesis of b-caryophyllene,23 the McMurry reaction
conditions have not been reported to induce geometric
isomerization of existing double bonds. No geometrical or
positional isomerization has been observed during the
intramolecular coupling reactions of keto-aldehyde
reactants.24 Thus the three products of the McMurry
coupling of 18 were expected to retain the (E)/(Z) ratio of
the substrate in the pre-existing double bond. Given the
dominance of the (Z) isomer in the substrate and the
approximate 1:1:1 ratio of triene products, it seemed likely
that the (Z)-form of 18 had reacted to yield the (4Z,8Z)-
triene 7 and the (4Z,8E)-triene 8, while the (E)-isomer of 18
had reacted with a high degree of stereoselectivity to yield
either the desired (4E,8E)-triene 4 or its (4E,8Z)-isomer.
This hypothesis was consistent with the results of a
dicarbonyl coupling reaction completed with a 1:1 mixture
of the isomers of 18. Here, GC revealed a ca. 1:1:2 ratio of
the same triene products.
McMurry coupling (Scheme 5) was initially achieved by
using a modification of the procedures reported for the
synthesis of humulene20 and cyclotridecene,21 and
employed 8 equivalents of titanium trichloride with a
3.1:1 ratio of Zn/Cu couple to titanium trichloride. Keto
aldehyde 18 with an (E)/(Z) ratio of 1:2.4 was added via
syringe pump. GC of the product revealed approximately
equal amounts of three components of similar retention
index. GC/MS showed similar mass spectra for each peak,
with the highest ion recorded at 257 Da, corresponding to a
loss of CH3 (b-caryophyllene (5) exhibits similar facile loss
Although reverse phase chromatography has been applied
successfully to the separation of the geometric isomers of
casbene,22 no such separation of 4, 7 and 8 was attained.
However, the three isomers were separated by centrifugal
chromatography on silver nitrate impregnated silica. Two
components eluted with 3:97 ethyl acetate/hexanes, and the
third with 3:17 ethyl acetate/hexanes. This latter com-
ponent, the (4Z,8E)-triene 8, had the greatest signal
1
of CH3). The H NMR spectrum, though complicated by
peak overlap, suggested that cyclization had taken place as
desired. Although no starting material or pinacol species
were detected, the isolated yield of trienes was only 20%.
1
dispersion in the H NMR spectrum and proved to be the
most amenable to full structural characterization.
The synthesis of casbene22 appeared to offer a good analogy
for the cyclization of 18. This synthesis involved the
coupling of a methyl ketone with an aldehyde, a 14-
membered ring fused to a small ring with a gem-dimethyl
unit was formed, and apart from the two reacting carbonyls,
only alkene functional groups were present. Cyclization of
18 was achieved in a 30% yield by the use of 40 equivalents
of titanium trichloride. This was increased to 52% by
increasing the reagent preparation time and by adding the
substrate more slowly.
HRMS data for triene 8 were consistent with the expected
molecular formula, C20H32. The solution IR spectrum was
compatible with an unsaturated hydrocarbon and 1H and 13
C
NMR spectroscopy (Table 1) revealed the presence of 1,1-
disubstituted and trisubstituted (!2) double bonds in accord
with a bicyclic structure.
Long range correlations from the proton resonances at dH
1.04, 1.02 to a quaternary carbon signal at dC 33.3 were

S. F. R. Hinkley et al. / Tetrahedron 61 (2005) 3671–3680
Table 1. NMR data for isomeric trienes 4, 7 and 8a
3675
Position
dC
7 (4Z,8Z)
dH [LRHETCORc]
b
4 (4E,8E)
8 (4Z,8E)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
45.3
27.3
35.4
50.7
28.0
28.8
47.1
25.1
29.1
136.2
125.3
29.6
38.3
136.9
124.6
30.5
34.4
152.4
41.2
41.0
33.3
30.6
22.6
108.7
22.6
19.1
1.92, ddd, 9.5, 10, 10 [n.o.]
2.12 [n.o.]; 2.29 [C-3]
1.73 [n.o.]; 2.27 [C-4, 4-Me]
—
5.12, br dd, 7,7 [n.o.]
1.73 [n.o.]
1.82 [n.o.]; 2.12 [n.o.]
—
5.05, br dd, 6.5, 11 [n.o.]
2.10 [n.o.]
2.17 [C-10, C-12, 12-]CH2]
—
2.34 [C-2]
1.35, dd, 9.5, 10 [C-12, 15b-Me]; 1.85, dd, 10, 10 [n.o.]
—
1.04, s [C-1, C-15, 15a-Me]
1.02, s [C-14, C-15, 15b-Me]
4.78, s [C-13]; 4.87, d, 1.5 [C-11]
1.64, s [C-3, C-4, C-5]
133.5
124.2
24.5*
39.1
133.7
125.6
25.0*
31.4
149.7
43.5
36.3
33.7
31.4
137.9†
124.5‡
30.9
31.5
136.9†
124.0‡
33.2
37.3
153.7
41.2
39.4
33.3
30.8
15b-Me
15a-Me
12-]CH2
4-Me
8-Me
23.3
23.0
108.6
15.1
16.9
108.4
23.8*
23.6*
1.61, s [C-7, C-8, C-9]
*,†,‡Values marked with the same symbol within a column may be interchanged.
a Recorded in CDCl3 at 75 MHz (13C) or 300 MHz (1H), referenced to TMS.
b Chemical shift in ppm, multiplicity, coupling constants in Hz.
c Correlations from proton to signal to designated carbon signal, n.o.—none observed.
consistent with a gem dimethyl unit. Generation of
substructure 8a was enabled by LRHETCOR correlations
from the methyl proton signal at d 1.02 to a methylene
carbon signal at dC 41.0, and from that at d 1.04 to a methine
carbon signal at dC 47.1.
respectively). A proton signal associated with the latter of
these (dH 2.27) correlated to the carbon signal of a further
methylene group (dC 25.1). This gave rise to two further
subunits 8c and 8d. The carbon chemical shifts of the two
allylic methyl groups were consistent with an (E) geometry
for the double bond of 8c and a (Z) geometry for that of
8d.14 These four substructures 8a–d encompassed 19 of the
20 carbons.
A further substructure 8b was generated based on chemical
shift data, and LRHETCOR correlations. A correlation from
one of the olefinic methylene proton signals (dH 4.78) to a
methine carbon signal at dC 41.2 and one from the allylic
methylene proton signal at dH 2.17 to the olefinic carbon
resonances at dC 108.7 (t) and 152.4 (s) established the
nature of the carbons adjacent to the 1,1-disubstituted
double bond. The proton signal at dH 2.17 also correlated to
a further methylene carbon (dC 30.5) associated with an
allylic proton signal (dH 2.10).
NMR shift data for the carbons of subunit 8a indicated that
it was, as expected, part of a four-membered ring. The
structure of the starting material implied the union of
fragments 8a and 8b to form a cyclobutane ring. The
coupling pattern observed for the ring methylene proton
signals (dH 1.35, dd, JZ9.5, 10 Hz; 1.85, dd, JZ10, 10 Hz)
concurred with this proposal. LRHETCOR correlation
The 1H NMR spectrum displayed two allylic methyl signals
at dH 1.61 and 1.64. Each showed LRHETCOR correlation
to a methylene carbon signal (dC 38.3 and 29.1
between the proton signal of the methine group of 8b (dH
2.34) and the carbon signal of the terminal methylene unit of
8d (dC 25.1) added further weight to this assertion and

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allowed the addition of subunit 8d as in substructure 8e. The
methylene group in substructure 8c is not part of
substructure 8e and this, together with only unplaced
methylene group (dH 1.73, dC 29.6), was required to
complete the ring as in structure 8.
30 mL minK1. Sample size was 0.1 mL and a sample split
ratio of w20:1 was used. Kovats retention indices27 were
determined from isothermal runs at 170 and 190 8C.
4.1.2. Instrumentation. NMR spectra were recorded on a
Varian VXR-300 spectrometer operating at 300 MHz for 1H
and 50 MHz for 13C. Spectra were obtained at 25 8C on ca.
0.075 M CDCl3 solutions and were referenced to the CHCl3
peak (d 7.26) for 1H, or to the centre line of the CDCl3 signal
(d 77.08) for 13C. LRHETCOR spectra were optimised for
long range coupling of 6–10 Hz. IR spectra were recorded
on a Perkin–Elmer 1600 series FT IR instrument. Optical
rotations were measured as CHCl3 solutions using a Jasco
DIP-370 digital polarimeter.
The first isomer to elute from the silver nitrate plate, had
very similar HRMS and IR spectra to those of 8. The most
significant difference between the 13C NMR spectra of the
two isomers was the chemical shift of the peaks assigned to
the methyl groups of the trisubstituted double bonds (dC
15.1 and 16.9 compared to dC 19.1 and 22.6 for 8). Thus,
both double bonds have the (E) geometry as in the desired
structure 4.14 Observed LRHETCOR correlations were
consistent with this structure.
4.1.3. Inert gas purification. Dry, oxygen free argon (1 to
10 ppm O2) was prepared by passing argon (NZIG gas code
130) through a column (45!500 mm) packed with BASF R
3-11 catalyst. The catalyst was reduced prior to use by
slowly passing a stream of H2 through the pellets and
increasing the temperature to 140 8C over 4 h, then
maintaining this temperature for 12 h. The catalyst
was then dried (200 8C/0.2 mm Hg, 12 h) and the column
was connected to the two stage argon cylinder valve. H2O was
removed by a second column (35!240 mm) packed with
Drierite indicator and powdered P2O5. All solvent transfers
requiring dry conditions were done using Schlenck
apparatus under dry argon and using standard vacuum line
techniques. Glassware was flame dried three times. For the
McMurry reaction, glassware was also heated overnight at
120 8C and ground glass joints were immediately fitted with
a Teflonw sleeve and connected to vacuum prior to flame
drying. Molecular sieves (new and recycled) were dried
(180 8C, 0.2 mm Hg) for 10 h prior to use.
The remaining isomer was assigned the (4Z,8Z) stereo-
chemistry 7 on the basis of the chemical shifts of the two
olefinic methyl carbon signals (dC 23.6, 23.8). Resonances
(Table 1) were assigned with the aid of LRHETCOR
correlations and by comparison of chemical shifts with
those of 4 and 8.
3. Conclusions
The synthesis of the caryophyllene isoprenologue 4 with the
(4E,8E) geometry has now been completed. This has also
yielded the (4Z,8Z) and (4Z,8E) isomers 7 and 8. Overall,
(K)-b-caryophyllene (5) has been converted into a 1:1:1
mixture of 4, 7 and 8 in a 25% yield. Compound 4 is a
potential natural product, structurally related to the marine
metabolite, flexibilene 23 as humulene 6 is to caryophyllene
5. The GC retention, MS and NMR data presented here will
allow rapid identification of 4, or isomers 7 and 8, from
natural sources. However, any intention to explore possible
connections between 4 and laurenene 1, must await a
synthesis that is more amenable to scale-up.
4.1.4. Solvent purification. For the Wittig reactions, THF
was refluxed for 2 h and freshly distilled from Na/K
amalgam under an argon atmosphere. DMSO was distilled
˚
under reduced pressure, shaken overnight with 4 A
NMR spectra of the bicycle [11.2.0] compounds 4, 7 and 8
showed no significant line broadening in contrast to the
bicyclic [7.2.0] compound, caryophyllene (5)25,26 where the
smaller ring resulted in slowly exchanging rotational
isomers.
molecular sieves then redistilled on to fresh molecular
sieve and stored under dry argon. For the McMurry
reactions, potassium was cut under hexane and transferred
quickly to a distillation apparatus that had been heated
overnight in an oven (120 8C) and then purged with dry
argon. DME was then refluxed for 10 h over potassium
under dry argon and then distilled onto fresh potassium. The
DME was then refluxed over potassium under dry argon for
a further 4 h before use in subsequent reactions. Acetone
4. Experimental
˚
4.1. General methods
was distilled from 4 A molecular sieves onto fresh sieve and
stored under dry argon for 1 week prior to use. Et2O was
freshly distilled from LiAlH4 under dry argon.
4.1.1. Chromatography. TLC was performed on silica gel
60 F254 0.2 mm coated aluminium foil. Centrifugal
chromatography was performed on a Harrison Research
7942T Chromatotron with plates coated with 1, 2 or 4 mm
layers of silica gel 60 PF254 with CaSO4$1⁄2H2O applied as a
slurry and dried. 4 mm Silver (I) impregnated plates were
made by including AgNO3 (5 g) into the slurry. Column
chromatography used silica gel 60. GC was performed using
a Hewlett–Packard HP 6890 series capillary gas chromato-
graph fitted with a programmable temperature injector
(250 8C) and a flame ionisation detector (260 8C). A 30 m!
0.32 mm HP-1 column (0.25 mm film thickness) was used
with helium as carrier gas at 8 PSI with a flow rate of
4.1.5. Zn/Cu couple. Zinc dust (489 g) was stirred with
aqueous HCl solution (2%, 1500 mL) for 5 min then washed
with aqueous HCl solution (2%, 1000 mL), H2O (3!
500 mL), EtOH (2!750 mL) then Et2O (2!500 mL). The
solvents were decanted from the dust in each case. The
resultant light grey powder was dried (100 8C/12 mm Hg)
for 3 h. A portion was weighed into a conical flask
(127.08 g, 2 mol), and a glass filter tube with sinter (grade
4) was fitted. The vessel was evacuated for 1 h and then an
argon atmosphere introduced and the equipment evacuated
and flushed with argon three times. H2O (500 mL) was

S. F. R. Hinkley et al. / Tetrahedron 61 (2005) 3671–3680
3677
introduced and the slurry purged with argon for 10 min.
CuSO4$5H2O (11.2 g, 63 mmol) was added and the reaction
mixture shaken. After 5 min the solids were collected by
filtration and washed with acetone (200 mL), then Et2O
(200 mL), and the dark grey material was dried
(100 8C/0.2 mm Hg, 5 h) before being stored under dry
argon.
mixture of benzene (30 mL), p-toluenesulfonic acid (32 mg,
0.017 mmol) and 1,3 propanediol (0.647 g, 8.5 mmol) was
added keto-aldehyde 9 (2.0 g, 8.5 mmol). The reaction was
fitted with a Dean–Stark trap and heated under reflux for 2 h.
The reaction mixture was cooled, washed with satd aqueous
NaHCO3 solution (35 mL), the aqueous layer extracted with
ether (2!10 mL) and the combined organic portions dried.
Evaporation gave an oil (2.40 g) which, on centrifugal
chromatography (Et2O/hexanes; 1:1) gave 11 (1.9 g, 80%)
as a clear liquid; 1H NMR0d00 0.99 (s, 20-Me), 1.00 (s, 20-Me),
1.30 (m, Wh/2Z2 Hz, H-5 ), 1.39 (t, JZ10 Hz, H-30), 1.54
(dt, JZ8, 8 Hz, 2!H-4), 1.64 (m, 2!H-300), 1.75 (m, H-30),
1.82 (m, H-10), 2.00 (m, 2!H-200), 2.05 (m, H-5000), 2.07 (s,
3!H-1), 2.29 (m, 2!H-3), 2.32 (m, H-40), 3.70 (ddd, JZ3,
12, 12 Hz, H-4000, 6000), 0400 .05 (dd, JZ50,0 12 Hz, H-4000, 6000),
4.47 (t, JZ5.5 Hz, H-2 ), 4.65 (brs, 1 -]CH2), 4.69 (brs,
100-]CH2); 13C NMR d 22.4 (q, 20-Me), 24.7 (t, C-4), 25.8
(t, C-50000), 28.7 (t, C-200), 29.8 (q, C-01), 31.0 (q, 20-Me), 33.5
(s, C-2 ), 33.5 (t, C-300), 39.9 (t, C-3 ), 41.6 (d, C-40), 42.000(0t,
C-3), 47.800(d, C-10), 66.9 (t, C-3000, 6000), 101.9 (d, C-2 ),
106.9 (t, 1 -]CH2), 151.9 (s, C-100), 208.8 (s, C-2). Anal.
Calcd for C18H30O3: C, 73.4; H, 10.3. Found C, 73.1; H,
10.2.
4.1.6. (K)-b-Caryophyllene (5). Commercial b-caryophyl-
lene (ex BDH) was purified by silica column chromato-
graphy, eluting with hexanes, to remove humulene and
oxidised material.
4.2. Synthetic methods
4.2.1. (10S,20R)-3,3-Dimethyl-4-methylene-2-(3-oxo-
butyl)cyclobutanebutanal (9).5 {CN 101979-01-5} A
solution of (K)-b-caryophyllene (5) (5.0 g, 24.3 mmol) in
EtOAc (50 mL) was dissolved in MeOH (500 mL) contain-
ing hexadecane (0.1 g) and treated with dry, ozonised
oxygen at K78 8C. The reaction was monitored by GC.
After 35 min there was no diene present with respect to the
internal standard (hexadecane). After excess ozone had been
removed by purging with nitrogen, Me2S (5 mL) was added,
and the reaction mixture was stirred for 12 h. Evaporation
followed by column chromatography, eluting with Et2O,
gave 9 (2.4 g, 041%) as a clear oil; IR as in Ref. 5; 1H NMR d
1.05 (s, 2!3 -Me), 1.41 (dd, JZ7, 8 Hz, H-40), 1.63 (m,
Wh/2Z13 Hz, 2!H-400), 1.80 (H-40), 1.86 (m, H-20), 2.12 (s,
3!H-100), 2.31 (m, 2!H-2, 2!H-3 and H-10), 2.57 (m,
Wh/2Z7 Hz, 2!H-300), 4.69 (s, 4-]CH2), 4.78 (s,
4.2.4. (30E,100R,400S)- and (30Z,100R,400S)-2-{6-[4-(4,4-
Dimethoxy)-1-methylenebutyl)-2, 2-dimethylcyclo-
butyl]-4-methyl-3-hexenyl}-2-methyl-1,3-dioxolane (14).
(a) n-BuLi (871 mL, 1.4 M, 1.22 mmol) was added dropwise
over 5 min to a stirred suspension of phosphonium salt 1210,11
{CN 21955-58-8} (0.580 mg, 1.11 mmol) in THF (20 mL)
at K85 8C. After stirring for 5 min the solution was warmed
to room temperature. After stirring for 10 min the bright
orange/red solution was cooled to K85 8C and keto acetal
10 (0.300 g, 1.12 mmol) in THF (3 mL) was added dropwise
over 5 min. The mixture was warmed to room temperature
and stirred for 3 h before being diluted with H2O (35 mL)
and extracted with Et2O (3!10 mL). Drying over anhyd.
MgSO4 and evaporation gave a yellow oil (0.350 g).
Centrifugal SiO2 chromatography (hexanes to Et2O/
hexanes; 1:1) gave a mixture of the (E) and (Z) isomers of
14 (5:11 by GC) (0.292 g, 66%). Further centrifugal
chromatography on a sub-sample (!2, hexanes to Et2O/
hexanes; 3:1) yielded an enriched fraction of 14 with a 1:6
(E)/(Z) ratio by GC; IR (neat) nmax 1039 (C–O), 924
(CH]C), 875 (CH2]C) cmK1; MS (EI) m/z (%)
379 (MCKCH3, 5%), 362 (MCKMeOH, 5%), 347
(MCKC2H7O, 5%), 330 (MCK2MeOH, 5%). NMR
spectra of mixtures of various compositions allowed
assignment of most of the resonances for the two isomers.
13
4-]CH2), 9.75 (s, H-1); C NMR d 22.0 (30-Me), 240.2
(C-400), 26.2 (C-3), 29.5 (C-100), 30.7 (30-Me), 33.3 (C-30),
39.3 (C-40), 41.2 (C-10), 41.5 (C-300), 41.5 (C-2), 47.4 (C-2 ),
107.2 (4-]CH2), 150.3 (C-4), 201.7 (C-1), 208.3 (C-200).
4.2.2. (10R,40S)-4-[4-(4, 4-Dimethoxy-1-methylenebutyl)-
2, 2-dimethylcyclobutyl]-butan-2-one (10).5 {CN 101927-
11-1} MeOH (170 mL) was added to a solution of
commercial (K)-b-caryophyllene 5 (3.0 g, 70% 5 by GC,
10.2 mmol) in EtOAc (10 mL) and the mixture was treated
with dry, ozonised oxygen at K78 8C for 10 min. After
excess ozone had been removed by purging with nitrogen
and the solution had warmed to room temperature, Me2S
(5 mL) and Montmorillonite K-10 clay (3 g) were added,
and the reaction mixture was stirred for 48 h. Filtration,
evaporation, followed by column chromatography on silica,
eluting with Et2O/hexanes, 1:1, gave 10 (1.6 g, 59%) as a
clear oil, distilled 85 8C/0.02 mm Hg; [a]2D4 51.28 (CHCl3, c
1.0); IR as in Ref. 5; 1H NMR d 1.04 (0s, 20-Me), 1.05 (s, 20-
Me), 1.43 (dd, JZ10.5, 10.5 Hz, H-3 ), 1.65 (m, 2!H-4),
1.72 (m, 2!H-200), 1.80 00(m, H-30), 1.88 (m, H-10), 2.01
(m, Wh/2Z19 Hz, 2!H-3 ), 2.11 (s, 3!H-1), 2.35 (m, 2!
H-3), 2.38 (m, H-40), 3.32 (s, 2!OMe), 4.36 (t, JZ6 Hz,
H-400), 4.72 (s, 100-]CH2), 4.75 (s, 100-]CH2); 13C NMR d
22.4 (20-Me), 24.7 (C-4), 29.4 (C-300), 30.0 (C-1), 300.8
(20-Me), 31.1 (C-200), 33.6 (C-20), 39.9 (C-30), 41.6 (C-4 ),
42.1 (C-3), 47.9 (C-10), 52.7 (2!OMe), 104.2 (C-400), 107.0
(100-]CH2), 151.9 (C-100), 209.0 (C-2). Anal. Calcd for
C17H30O2: C, 72.3; H, 10.7. Found C, 72.5; H, 10.4.
1
The (Z)-isomer had: H NMR d 1.06 (s, 200-Me), 1.07 (s,
200-Me), 1.32 (s, 2-Me), 1.6070 (d, JZ1 Hz, 40-Me), 2.36
(ddd, JZ9.5, 9.5, 9.5 Hz, H-4 ), 3.32 (s, 2!OMe), 3.93 (m,
Wh/2Z7 Hz, 2!H-4 and 2!H-5), 4.37 (t, JZ8 Hz, H-4000),
4.71 (dd, JZ1, 1 Hz, 1000-]CH2), 4.76 (s, 1000-]CH2), 5.08
13
(ddd, JZ1, 8, 8 Hz, H-30); C NMR d 22.4 (200-Me), 22.7
(C-600), 23.05 (2-Me), 23.9 (40-Me), 290.05, 29.7, 30.6, 30.9
(C-1 , C-2 , C-2000 and C-3000), 31.4 (2 -Me), 33.8 00(C-200),
39.5, 39.6 (C-50 and C-300), 41.6 (C-400), 49.3 (C-1 ), 52.8
(2!OMe), 64.7 (C-4 and C-5), 104.3 (C-4000), 1060.9
(1000-]CH2), 110.0 (C-2), 124.1 (C-30), 136.0 (C-4 ),
152.2 (C-1000). The (E)-isomer had: 1H NMR d 1.04 (s,
200-Me), 1.05 00(s, 200-Me), 1.32 (s, 2-Me), 1.59 (s, 40-Me),
2.35 (m, H-4 ), 3.32 (s, 2!OMe), 3.93 (m, 2!H-4 and
4.2.3. (10R,40S)-4-[4-(3-[1, 3]Dioxan-2-yl-1-methylene-
propyl)-2,2-dimethylcyclobutyl]-butan-2-one (11). To a

3678
S. F. R. Hinkley et al. / Tetrahedron 61 (2005) 3671–3680
2!H-5), 4.37 (m, H-4000), 4.70–4.78 (m, 1000-]CH2), 5.06
centrifugal SiO2 chromatography (Et2O/hexanes; 1:9 to 1:1)
to give a mixture of the (E) and (Z) isomers of 15 (1:2.3 by
GC) (0.0.041 g, 40%); IR (neat) nmax 1042 (C–O), 922
(CH]C), 875 (CH2]C) cmK1; 1H NMR d 1.03, 1.04,0010 .06,
1.07 (each s, 300-Me), 10.030 3 (s, 2000 0-Me), 1.58 (brs, 3 -Me
(E)-isomer), 1.66 (br0s0, 3 -Me (Z)-isomer), 2.36 (brddd, JZ
9.5, 9.5, 9.5 Hz, H-1 ), 3.72 (ddd, JZ3, 12, 12 Hz, H-4, 6),
3.93 (m, Wh/2Z6 Hz, 2!H-40000, 2!50000), 4.10 (dd, JZ5,
13
(m, H-30); C NMR d 15.9 (40-Me), 33.7 (C-200), 41.6
(C-400), 48.5 (C-100), 50200.8 (2!OMe), 64.7 (C-4 and C-5),
104.3 (C-4000), 106.8 (1 -]CH2), 109.9 (C-2), 123.7 (C-30),
135.5 (C-40), 152.2 (C-1000) (other peaks obscured by
overlaps with signals of the (Z)-isomer). A microanalytical
sample was prepared by prep. TLC (CHCl3) followed by
microdistillation at 90 8C/4!10K4 mm Hg). Anal. Calcd
for C24H42O4: C, 73.1; H, 10.7. Found C, 73.1; H, 11.0.
12 Hz, H-4, 6), 4.50 (t, JZ8 Hz, H0-002), 4.70 (m, Wh/2
Z
13 Hz, 2!H-40), 5.05–5.15 (m, H-400 ); 13C NMR d 15.9
(3000-Me (E)-isomer), 48.5, 49.3 (C-2 ), 64.7 (C-40000, 50000),
66.90 (C-4, 6), 102.1 (C-2), 106.9 (C-20000), 109.9, 110.0
(C-4 ), 123.7, 124.1 (C-4000), 135.6, 136.1 (C-3000), 152.2,
152.3 (C-30). Anal. Calcd for C25H42O4: C, 73.9; H, 10.4.
Found C, 73.6; H, 10.7.
(b) n-BuLi in hexanes (1.0 mL, 1.54 M, 1.52 mmol) was
added dropwise over 5 min to a stirred solution of phosphine
oxide 1312 {CN 87109-17-9} (0.456 g, 1.38 mmol) in THF
(20 mL) at K78 8C. After stirring for 2 min the solution was
warmed to 0 8C. After stirring for 15 min the deep red
solution was cooled to K78 8C and a solution of keto acetal
10 (0.390 g, 1.38 mmol) in THF (7 mL) was added dropwise
over 2 min. The solution decolourised, was warmed to room
temperature, stirred for 5 min then quenched with saturated
NH4Cl (20 mL) and extracted with Et2O (3!15 mL).
Drying of the combined organic phases over anhyd.
MgSO4 and evaporation gave a pale yellow solid
(0.964 g). Centrifugal chromatography (EtOAc to EtOH/
EtOAc; 1:9) gave: (i) a mixture of diastereoisomers of the
diphenylphosphinoyl alcohols 16 (0.350 g, 41%); IR (nujol)
(b) Keto acetal 11 (0.100 g, 0.25 mmol) in THF (1 mL) was
reacted with the phosphine oxide 13 as for the reaction of
10. The anion was prepared from n-BuLi in hexanes
(177 mL, 1.55 M, 0.27 mmol), 1312 (0.082 g, 0.25 mmol) in
THF (4 mL). A semi-solid (0.188 g) was separated by
centrifugal chromatography (EtOAc to EtOH/EtOAc; 1:9)
to give: (i) phosphinoyl alcohol 17 isomer fraction 1
(0.028 g, 15%); 1H NMR† d 1.00, 0.96 (each 3H, s, 300-Me),
1.02 (3H, s, 3000-Me), 1.17 (3H, s, 020000000-Me), 1.25–2.45 (m),
3.10–3.35 (6H, m, H-4, 6, 40000, 5 ), 4.10 (2H, dd, JZ5,
12 Hz, H-4, 6), 4.50 (1H, t, JZ6.5 Hz, H-2), 4.69 (2H, brs,
nmax 3350 (OH), 1549, 1481, 1460, 1261, 1170, 750 cmK1
;
1H NMR† d 0.84, 0.88 (both s, 200-Me), 0.96, 0.98, 1.04 (all
s, 40-Me), 1.24, 1.27 (both s, 2-Me), 1.25–2.25 (m,
unassigned), 2.32 (m, Wh/2Z9 Hz, H-30 and H-400), 3.31
H-40), 7.48 (6H, m, Wh/2Z18 Hz, Ph), 7.82 (4H, m, Wh/2
Z
32 Hz, Ph); 13C NMR d 20.5–46.5 (multiple peaks), 48.9
(C-200), 64.4 (C-40000, 50000), 66.9 (C-4, 6), 706000.1, 76.2 (C-3000),
102.1 (C-2), 106.6 (C-40), 109.2 (C-2 ), 134.0–128.5
(multiple peaks, Ph), 152.2 (C-30); (ii) phosphinoyl alcohol
17 isomer fraction 2 (0.028 g, 15%); 1H NMR† d 0.98, 0.95
(each 3H, s, 300-Me), 1.01 (3H, s, 3000-Me), 1.19 (3H, s,
20000-Me), 1.20–2.45 (m), 3.70 (6H, m, Wh/2Z41 Hz, H-4, 6,
40000, 50000), 4.09 (2H, Wh/2Z26 Hz, H-4, 6), 4.50 (1H, t, JZ
7 Hz, H-2), 4.69 (2H, Wh/2Z8 Hz, H-40), 7.50 (6H, m,
Wh/2Z18 Hz, Ph), 7.81 (4H, m, Wh/2Z28 Hz, Ph); 13C
NMR d 20.5–46.5 (multiple peaks), 48.9 (C-200), 64.4
(C-40000, 50000), 66.9 (C-4, 06000), 76.5, 76.5 (C-3000), 102.0 (C-2),
106.9 (C-40), 109.1 (C-2 ), 134–128.5 (multiple peaks, Ph),
152.1 (C-30); (iii) unchanged keto acetal 10b (0.075 g,
72%).
(s, 2!OMe), 3.59–4.28 (m, H-4 and H-5), 4.34 (m, Wh/2
Z
15, H-4000), 4.52–5.00 (m, 1000-CH2), 7.48 (m, Wh/2Z14 Hz,
Ph, 6H), 7.79 (m, Wh/2Z36 Hz, Ph, 4H); 13C NMR† d 20.3–
49.2 (multiple peaks, unassigned), 52.6 0(OMe), 64.2, 64.4,
67.7000(C-4 and C-5), 75.8, 75.9 (C-4 ),000104.06, 104.11
(C-4 ), 106.5, 106.6, 106.7, 106.8 (C-1 ), 109.0 (C-2),
128.3–131.5 (several peaks, Ph), 151.8, 152.0 (C-1000);
(ii) starting material 10 (0.200 g, 55%). The reaction was
repeated on scales up to 1.0 g of 10.
To a stirred solution of the phosphinoyl alcohol mixture 16
(0.525 g, 0.858 mmol) in DMF (5 mL) was added NaH
(0.041 g, 60% in oil, 1.7 mmol) and the mixture was stirred
at 50 8C. After 1 h, TLC indicated that the starting material
had not been fully converted and additional NaH (0.040 g,
1.7 mmol) was added. After a further 1.5 h the mixture was
cooled, diluted with Et2O (10 mL), quenched with saturated
NaCl (50 mL) and extracted with Et2O (3!10 mL). Drying
over anhyd. MgSO4 and evaporation gave a brown oil
(0.569 mg) that on centrifugal chromatography (hexanes to
EtOH/EtOAc; 1:9) gave; (i) a mixture of the (E) and (Z)
isomers of 14 (1:1 by GC) (0.050 g, 16%); (ii) keto acetal 10
(0.045 g, 19%); (iii) unchanged 16 (0.240 g, 46%).
The less polar phosphinoyl alcohol 17 fraction (0.028 g,
0.039 mmol) in DMF (0.5 mL) was treated with NaH
(1.6 mg, 60% in oil, 0.039 mmol) as for the reaction of 16.
GC of the crude product revealed a 5:6 ratio of the (Z) to (E)
isomers of 15. The same ratio was obtained from the more
polar 17 fraction.
4.2.6. (10S,20R,300E)- and (10S,20R,300Z)-3,3-Dimethyl-4-
methylene-2-(3-methyl-7-oxoocta-3-enyl)cyclobutane-
butanal (18). A solution of the (E) and (Z) isomers of 14
(0.649 g, 1.65 mmol, ratio 1:1) in THF (30 mL) containing
aqueous HCl (2 M, 3 mL) was heated under reflux for
10 min. The mixture was cooled, quenched with saturated
Na2CO3 (30 mL), and extracted with Et2O (3!15 mL).
Drying and evaporation gave the (E) and (Z) isomers of 18
(1:1 ratio by GC) as a clear oil (0.467 g, 93%); IR (neat)
nmax 2725 (HC]O), 1714 (C]O), 1634 (C]C) cmK1; 1H
NMR d 1.05, 1.07 (both s, 30-Me), 1.59 (brs, 300-Me, (E)-
isomer), 1.66 (brd, JZ1 Hz, 300-Me, (Z)-isomer), 2.13 (s,
4.2.5. (3000E,100S,2R00)- and (3000Z,100S,2R00)-2-(3-{3, 3-
Dimethyl-2-[3-methyl-6-(2-methyl-[1, 3]dioxolan-2-yl)-
hex-3-enyl]-cyclobutyl}-but-3-enyl)-[1,3]dioxane (15).
(a) Keto acetal 11 (0.100 g, 0.25 mmol) in THF (1 mL)
was reacted with phosphonium salt 1210,11 as for the
reaction of 10. The ylide was prepared from n-BuLi
(177 mL, 1.55 M, 0.27 mmol), 12 (0.130 mg, 0.25 mmol)
in THF (4 mL). A yellow oil (0.200 g) was separated by
† Numbering as for 14.

S. F. R. Hinkley et al. / Tetrahedron 61 (2005) 3671–3680
3679
3!H-800), 4.67, 4.78, 4.80 (all brs, g-]CH2), 5.00–5.09 (m,
H-400), 9.77 (t, JZ2 Hz, H-1); 13C NMR low-field signals at
d 107.4, 107.5 (g-]CH2), 122.4, 122.8 (C-400), 136.6, 137.0
(C-300), 150.8 (C-4), 202.3 (C-700), 208.8 (C-1). A micro-
analytical sample was prepared by prep. TLC (CH2Cl2)
followed by microdistillation at 90 8C/1!10-3 mm). Anal.
Calcd for C20H32O2: C, 78.9; H, 10.6. Found C, 78.6; H,
10.7. A 5:11 mixture of the (E) and (Z) isomers of 16 was
formed similarly.
observed between d 1.27 (H-6) and both d 1.62 and 2.36
(H-7); 13C NMR see Table 1; MS (EI) m/z [%] 272 [9], 257
[8], 216 [10], 201 [6], 161 [12], 147 [10], 137 [5], 135 [12],
133 [22]; HRMS [MC] calcd for C20H32 272.2504, found
272.2506; (iii) with EtOAc/hexanes; 3:17, (4Z,8E)-diene 8
(0.069 g, 19%); [d]24 K848 (589 nm); K888 (577 nm);
K1038 (546 nm); K1948 (435 nm); K2458 (405 nm);
K1758 (365 nm) (CHCl3, c 0.99); GC RI 1839 (170 8C),
1860 (190 8C); IR (CCl4) nmax 2955, 2923, 2859, 1453,
1381 (C–H), 1640, 912 (C]C) cmK1 1H NMR see
;
Table 1; 13C NMR see Table 1; MS (EI) m/z [%] 272 [14],
257 [10], 216 [18], 201 [8], 161 [15], 147 [18], 137 [5],
135 [16], 133 [26]; HRMS [MC] calcd for C20H32
272.2504, found 272.2505.
4.2.7. (1R,4E,8E,13S)-, (1R,4Z,8Z,13S)- and (1R,4Z,
8E,13S)-4,8,15,15-Tetramethyl-12-methylenebicyclo-
[11.2.0]pentadeca-4, 8-dienes (4), (7) and (8). To a stirred
mixture of TiCl3 (8.14 g, 52.8 mmol) and Zn/Cu couple
(11 g, MrZ65.5, 169 mmol) was added dry dimethoxy-
ethane (120 mL). The mixture was gently simmered with
vigorous stirring for 17 h. At first a blue-green colour was
visible, but after w5 h a black suspension predominated. A
5:11 mixture of (E) and (Z) isomers of keto aldehyde 18
(0.408 g, 1.32 mmol) was first dried for 4 h under vacuum at
ambient temperature then dissolved in dry dimethoxyethane
(49 mL) and added to the reaction via syringe pump at a rate
of 0.54 mL hK1. After 4 days, the addition was complete.
The mixture was heated for a further 4 h, cooled, filtered
through a pad of Florisilw and evaporated to give a yellow
oil (0.482 g) containing three major components (1:1:1
ratio) by GC. Centrifugal chromatography on AgNO3
impregnated silica (!2, hexane to EtOAc/hexane; 7:13)
gave the following trienes listed in order of elution: (i) with
EtOAc/hexanes; 3:97, (4E,8E)-diene 4 (0.056 g, 16%);
[a]24 C428 (589 nm); C448 (577 nm); C508 (546 nm);
C838 (435 nm); C938 (405 nm); C618 (365 nm) (CHCl3, c
1.33); GC RI 1886 (170 8C), 1908 (190 8C); IR (CCl4) nmax
Acknowledgements
The Plant Extracts Research Unit, Crop and Food Research
is thanked for a scholarship (SFRH). Thanks to B. Clark,
University of Canterbury, New Zealand for MS, Mervyn
Thomas for NMR assistance, R. A. J. Smith, University of
Otago for the use of an indirect detection probe, and Mrs M.
Dick of the Campbell Microanalytical Laboratory,
University of Otago for microanalyses.
References and notes
1. Corbett, R. E.; Couldwell, C. M.; Lauren, D. R.; Weavers,
R. T. J. Chem. Soc., Perkin Trans. 1 1979, 1791–1794.
2. Chin, A. F. O.; Clarke, D. B.; Hinkley, S. F. R.; Perry, N. B.;
Weavers, R. T. Aust. J. Chem. 2001, 54, 205–211.
3. Herin, M.; Colin, M.; Tursch, B. Bull. Soc. Chim. Belg. 1976,
85, 801–803.
2928, 2860, 1461, 1381 (C–H), 1635, 921, 902 (C]C) cmK1
;
1H NMR [LRHETCOR] d 1.02 (s, 15a-Me) [15b-Me], 1.05
(s, 15b-Me) [15a-Me], 1.40 (m, W1/2Z19 Hz, H-2), 1.54 (s,
4-Me) [C-4, C-5], 1.55 (m, H-2), 1.58 (s, 8-Me) [C-8, C-9],
1.63 (m, 2!H-14) [15a-Me, C-12], 1.74 (m, H-3) [C-2,
C-5], 1.87 (ddd, JZ5.5, 9.5, 9.5 Hz, H-1), 2.01 (m, H-11),
2.04 (m, H-3), 2.08 (m, 2!H-7), 2.13 (m, 2!H-6), 2.21 (m,
H-11), 2.28 (m, 2!H-10), 2.50 (ddd, JZ9.5, 9.5, 9.5 Hz,
H-13) [C-2], 4.74 (s, 12-]CH2), 4.83 (s, 12-]CH2) [15b-
Me], 4.89 (dd, JZ6.5, 6.5 Hz, H-5), 5.21 (dd, JZ6.5,
6.5 Hz, H-9); 13C NMR see Table 1; MS (EI) m/z [%] 272
[11], 257 [17], 216 [15], 201 [10], 161 [19], 147 [19], 137
[10], 135 [20], 133 [29]; HRMS [MC] calcd for C20H32
272.2504, found 272.2507; (ii) with EtOAc/hexanes; 3:97,
(4Z,8Z)-diene 7 (0.063 g, 17%); [a]24 K238 (589 nm);
K258 (577 nm); K298 (546 nm); K618 (435 nm); K788
(405 nm); K318 (365 nm) (CHCl3, c 1.06); GC RI 1879
(170 8C), 1901 (190 8C); IR (CCl4) nmax 2958, 2861, 1461,
4. Bohlmann, F.; Jakupovic, J. Phytochemistry 1980, 19, 259–265.
5. Odinokov, V. N.; Kukovinets, O. S.; Isakova, L. A.; Zainullin,
R. A.; Dubovenko, Z. V.; Tolstikov, G. A. Zh. Org. Khim.
1985, 21, 992–997.
6. Node, M.; Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K.
Tetrahedron Lett. 1984, 25, 219–222.
7. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
8. Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
9. Findlay, J. A.; MacKay, W. D.; Bowers, W. S. J. Chem. Soc.
(C) 1970, 2631–2635.
10. Cavill, G. W. K.; Laing, D. G.; Williams, P. J. Aust. J. Chem.
1969, 22, 2145–2160.
11. Cavill, G. W. K.; Williams, P. J. Aust. J. Chem. 1969, 22,
1737–1744.
1379 (C–H), 1636, 900 (C]C) cmK1
;
1H NMR
[LRHETCOR] d 1.03 (s, 15b-Me), 1.04 (15a-Me), 1.27
(m, W1/2Z23 Hz, H-6), 1.56 (dd, JZ12, 12 Hz, H-14)
[C-12, 15a-Me, 15b-Me], 1.62 (m, H-7), 1.70 (s, 4-Me and
8-Me), 1.72 (m, H-1), 1.81 (m, H-6), 1.83 (dd, JZ12, 12 Hz,
H-14) [15a-Me], 1.84 (m, H-10), 1.85 (m, H-2), 1.90 (ddd,
JZ3, 10, 10 Hz, H-3), 2.09 (m, 2!H-11) [C-12], 2.10 (m,
H-10), 2.11 (m, H-3) [C-2], 2.36 (dd, JZ15, 15 Hz, H-7)
[C-4], 2.37 (m, H-2) [15a-Me], 2.52 (ddd, JZ9, 9.5, 9.5 Hz,
H-13) [C-12, 15b-Me], 4.71 (dd, JZ2, 2 Hz, 12-]CH2)
[C-11], 4.75 (d, JZ1 Hz, 12-]CH2) [C-13], 5.21 (dd, JZ8,
8 Hz, H-9), 5.23 (dd, JZ8, 8 Hz, H-5); COSY correlations
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