Isolation and chemistry of clerodane diterpenes from Dodonaea ceratocarpa

Article abstract of DOI:10.1016/j.tet.2016.09.062

A new clerodane was isolated from Dodonaea ceratocarpa and obtained in appreciable quantities (0.5% w/w plant). A variety of reactions on this clerodane provided access to a range of new derivatives, including cationic skeletal rearrangements and reduction reactions with lanthanide salt additives.

Full text of DOI:10.1016/j.tet.2016.09.062

Tetrahedron xxx (2016) 1e11
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Isolation and chemistry of clerodane diterpenes from Dodonaea
ceratocarpa
,
Vasoulla N. Moussa a, Brian W. Skelton b, Alan D. Payne a
*
a Department of Chemistry, Curtin University, Perth, WA 6945, Australia
b Centre for Microscopy, Characterisation and Analysis, University of Western Australia, Crawley, WA 6009, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2016
Received in revised form 14 September 2016
Accepted 27 September 2016
Available online xxx
A new clerodane was isolated from Dodonaea ceratocarpa and obtained in appreciable quantities (0.5%
w/w plant). A variety of reactions on this clerodane provided access to a range of new derivatives,
including cationic skeletal rearrangements and reduction reactions with lanthanide salt additives.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Dodonaea
Clerodane
Luche reduction
Rearrangements
1. Introduction
and gives pale brown to purple brown flowers in AugusteDe-
cember.9 The natural products of this plant have not been in-
The Dodonaea genus is a rich source of natural products contain-
ing di- and triterpenes, flavonoids and other polyphenols, long chain
fatty acids, saponins and sterols.1 A distinctive feature of this genus is
that they contain a wide variety of clerodane diterpenes 1. Clerodanes
are commonly found on the leaf resin of plants, and are mostly rec-
ognised for their insect antifeedant properties.2 They are named after
the insect antifeedant clerodin 2, which has the stereochemistry of
a neo-clerodane. Many clerodanes also have antibacterial3 and anti-
inflammatory properties.4 Recently the hydroxylactone clerodane 3,
known as PL3, isolated from Polyalthia longifolia var. pendula was
shown to be as good as lovastatin in the inhibition of HMG-CoA re-
ductase.5 Total synthesis of clerodanes is challenging,6 thus a semi-
synthetic7 approach is a more viable strategy for the preparation of
new derivatives from a suitable plant source and would enable future
screening of their medicinal properties (Fig. 1).
vestigated to date. This paper describes preliminary studies into the
isolation and structural elucidation of three main clerodane diter-
penes from D. ceratocarpa, as well as some preliminary reactions on
the major clerodane isolated from the leaf resin.
So far, only three species of the Dodonaea genus have produced
clerodane diterpenes (Dodonaea attenuata, Dodonaea boroniaefolia
and Dodonaea viscosa).8 Dodonaea ceratocarpa, commonly known
as horny hop-bush, is a native shrub in the Sapindaceae family
found at coastal regions of south-western Western Australia. Its
leaves are simple, sessile and oblanceolate, 1.1e7.0 cm long and
0.2e1.3 cm wide. This drought tolerant scrub grows to 2.5 m high
Fig. 1. Clerodane diterpene framework 1, clerodin 2 and PL3 3.
2. Results and discussion
2.1. Isolation
D. ceratocarpa was grown from seedlings in Balingup, Western
Australia. The aerial part of the plant was collected in Octo-
bereNovember over a 4 year period (2011e2014). The leaves of D.
* Corresponding author. Fax: þ61 8 9266 2300; e-mail address: alan.payne@
curtin.edu.au (A.D. Payne).
http://dx.doi.org/10.1016/j.tet.2016.09.062
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
ceratocarpa were steeped in diethyl ether at room temperature for
30 min to selectively remove the resin coating from the leaves. The
diethyl ether extract of the D. ceratocarpa leaves contained three
compounds (4e6, Fig. 2). Compounds 4 and 5 are unreported
clerodane diterpenes, whilst the third clerodane diterpene 6 has
been isolated from Croton sonderianus10 and Aylthonia macrantha.11
Fig. 3. X-ray structure of the alcohol 4. The minor component of the disordered atoms
has been omitted.
Fig. 2. Clerodanes isolated from the leaf resin of D. ceratocarpa.
similar to 4 but showed a pair of doublets at 4.03 and 4.28 ppm,
replacing the C18 allylic methyl in 4. The peaks attributed to the
butenolide were evident, however, H3 shifted downfield to
5.59 ppm, most likely due to the electron withdrawing nature of the
allylic alcohol. The 1H NMR data of 5 did not match the reported
clerodane with the cis arrangement,12 therefore the trans configu-
ration was assigned to 5. Clerodane 6 had a 1H NMR spectrum that
was similar to that of 4, with furanoid signals at 7.34 (1H, t),
7.19e7.22 (1H, m) and 6.25 ppm (1H, dd) instead of the butenolide
signals. In addition, an upfield shift of H3 was observed at 5.24 ppm
(1H, br s). The spectral data of the clerodane 6 matched the com-
pound reported by Silveira and McChesney.10
Clerodane 4 was isolated as a pale yellow powder and was the
most abundant, accounting for approximately 0.5% w/w of the total
plant mass. It had a molecular formula of C20H30O3, as deduced
from HRMS, [MþH]þ m/z found 319.2276. IR spectroscopy indicated
the presence of a hydroxyl group (3510 cmꢀ1) and a butenolide,
attributed by a higher carbonyl stretching frequency (1786 cmꢀ1).
The 1H NMR spectrum supported the presence of the butenolide
with two signals at 5.78e5.82 (1H, m) and 4.72 ppm (2H, s), which
have a correlation in the COSY spectrum. A vinylic signal on the
clerodane skeleton at 5.23 ppm (1H, s) was evident. A doublet of
doublets was observed at 3.53 ppm (1H), which indicated that the
proton was bound to a tertiary carbon adjacent to a methylene (H6).
Crystals suitable for X-ray analysis were obtained from a solution of
4 in diethyl ether and petrol. The crystal structure confirmed the
proposed structure. The A ring of 4 is in a chair conformation, with
the methyl (C19) and hydrogen (H10) at ring junction adopting an
anti-arrangement (Fig. 3). C17 and C19 methyl groups adopted an
axial conformation that is distorted due to the steric hindrance of
the congested bottom face of the molecule. The hydroxyl group at
All of the clerodane diterpenes isolated in this study on D.
ceratocarpa were found to contain a trans arrangement, at the
decalin ring junction (5
counterpart in the Dodonaea genus.13 Another recurring feature of
all three of the isolated compounds is the -orientation of the C6
a,10b), which is more common than the cis
a
hydroxyl group. Only one clerodane isolated from the Dodonaea
genus has this particular feature.14 The similar structures of com-
pounds 4, 5 and 6 could be concomitant with their biosynthesis in
the plant (Scheme 1). The furan 6 could be oxidised to the bute-
nolide form 4. Allylic oxidation of 4 could then allow formation of 5.
C6 was in the
a-orientation and equatorial, making this alcohol
Scheme 1. Potential biosynthetic relationship between 4, 5 and 6.
sterically congested. In the unit cell the equatorial hydroxyl group
O6 forms a hydrogen bond with the butenolide oxygen atom O15 of
the molecule generated by a crystallographic 21 screw (H(6) .
2.2. Oxidation and reduction reactions
From 200 g of D. ceratocarpa, 1 g of compound 4 was isolated.
Since 4 could be isolated in gram quantities, its chemistry was in-
vestigated. It was discovered that 4 decomposed to a complex
mixture of products when stored neat at room temperature. Oxi-
dation of 4 with pyridinium chlorochromate (PCC) afforded the
ꢀ
O(15)¼2.07 A).
Clerodane 5 has a molecular formula of C20H30O4 by HRMS. IR
spectroscopy presented
a
broad hydroxyl group stretch
(3354 cmꢀ1) and butenolide stretches. The 1H NMR spectrum was
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V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
3
stable ketone 7 in 99% yield (Scheme 2). The ketone 7 was a versatile
of Lewis acidity of the lanthanide salts.
intermediate and was used as a starting material along with the
alcohol 4. The reversibility of the aforementioned oxidation reaction
was studied. Reduction of 7 with sodium borohydride in methanol
gave 8, the b-alcohol, in 90% yield. The major difference noted be-
tween this product and the isolated alcohol 4 was that the
signal attributed to 8 appeared at 3.85 ppm (t), whereas the
a
b
-H6
-H6
signal for 4 appeared at 3.53 ppm (dd). To further support the
structure of 8, it was oxidised with PCC to provide the ketone 7 in
83% yield. This result is counterintuitive since the hydride has added
from the more hindered face of the molecule. However, molecular
models show that the ketone adopts an orientation resembling the
axial position, leaving the bottom face exposed to hydride addition.
A similar stereoselective reduction has been reported on a C6 ketone
in clerodanes, but lower yields were obtained.10
Transition metal chlorides additives were also used with sodium
borohydride under the same conditions. The reactions with ZnCl2,
SnCl4 and CuCl gave the b-alcohol 8 quantitatively with 100% se-
Sodium borohydride reductions with lanthanide additives can
modify the selectivity of hydride addition to a carbonyl group. Krief
Scheme 2. Oxidation and reduction reactions.
and Surleraux have demonstrated the addition of CeCl3 salts can
affect the stereochemical outcome of the hydride reduction re-
action.15 When the ketone 7 was subjected to 1 equiv of sodium
borohydride and 1 equiv of CeCl3 in methanol at ꢀ84 ꢁC, a mixture
of the two epimeric alcohols 4 and 8 at C6 were formed in 98% yield
with a 49:51 ratio (Table 1). Using a representative selection of
chlorides from the lanthanide series (LaCl3, SmCl3, EuCl3, TbCl3 and
YbCl3), this effect on selectivity was studied further. Treatment of
the ketone 7 with 1 equiv of sodium borohydride and 1 equiv of
LnCl3 hydrate afforded mixtures of 4 and 8 in yields of 98e100%.
lectivity, so these additives had no effect on the outcome of the
reaction. The addition of PdCl2 also gave the -alcohol along with
hydrogenated butenolide 9 in 100% yield (Table 2). Similar re-
actions have been achieved with sodium borohydride and palla-
dium on carbon on chalcones but not with more complex
molecules such as clerodanes.16
In all of the previous examples, the butenolide remained intact.
Treatment of 4 with 3 equiv of lithium aluminium hydride in tet-
rahydrofuran gave the triol 10 as a mixture of two diastereomers
(Scheme 3). The C13eC14 alkene was also reduced in this reaction.
A doublet of doublets was found at 3.53 ppm in the 1H NMR
spectrum assigned to H6. Peaks at 3.46e3.49 (1H, m) and 3.64 ppm
(1H, dt) were observed attributed to the H16 methylene attached to
an alcohol. A multiplet at 3.67e3.78 ppm was ascribed to the H15
methylene attached to the other alcohol. The 13C NMR spectrum
gave two resonances at 66.52 and 66.56 ppm which were assigned
to the primary alcohol at C16.
b
The
a-alcohol 4 was formed in relative percentages of 14e54%.
Thus, the lanthanide chloride additives enabled the formation of 4
but could not completely reverse the inherent selectivity of the
NaBH4 reaction. A trend was observed across the lanthanide series.
Lanthanum salts gave the highest ratio of
and ytterbium salts gave the lowest ratio. As the additives moved
across the lanthanide series the reversal of selectivity for the
a and b-alcohols, 4 and 8,
a
-
alcohol becomes less pronounce, which coincides with a reduction
Table 1
Reductions of 7 with NaBH4 and LnCl3 additives
LnCl3 $xH2O
Yield
Ratio
4 (
a
)
8 (b)
None
YbCl3
TbCl3
EuCl3
SmCl3
CeCl3
LaCl3
90%
100%
99%
100%
100%
98%
0
100
86
78
74
68
51
46
14
22
26
32
49
54
98%
Scheme 3. Reduction of the butenolide.
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V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
with sulfuric acid, and the formation of halimane.7a,17 Based on
Table 2
Reductions of 7 with NaBH4 and MClx additives
these reactions the most probable mechanism for this reaction is as
follows: (i) protonation of the alkene to give the 3ꢁ carbocation 13;
(ii) a 1,2-methyl shift of C19 to the C4 position gives 14; (iii) a 1,2-
hydride shift to the new bridgehead carbocation; and (iv) loss of Hþ
to generated the ketone 12. Based on this mechanism the stereo-
chemistry of H5 at the ring junction was assigned to a
as it had the same orientation as H6.
b-orientation
When the alcohol 4 was reacted with PCl5 a different rear-
rangement was observed (Scheme 5). When PCl5 was added to
a solution of 4 and sodium carbonate in anhydrous dichloro-
methane, two compounds of a lower polarity than the starting
material were isolated immediately after workup. One of the
products was the chloride 16, however it rapidly rearranged to the
azulenic framework 17 over a couple of hours, which was isolated
in 99% yield. The 1H NMR spectrum of 17 was quite different from
the starting alcohol 4, both resonances associated with the H3 and
H6 were absent and there were no signals above 2.50 ppm other
than the signals associated with the butenolide. The 13C NMR
spectrum of 17 showed four new quaternary signals at 127.5, 134.8,
138.9 and 144.7 ppm suggesting a 1,3-diene. The chemical shifts for
the four methyl groups were observed at 0.85, 0.96, 1.67 and
1.83 ppm and the latter two were identified as allylic. The proposed
mechanism of this PCl5 mediated rearrangement of 4 to 17 is as
follows (Scheme 5): the hydroxyl group is substituted for a chloride
with retention of stereochemistry, which has been observed with
PCl5 in tertiary alcohols18a and hindered secondary alcohols as part
of a Grob fragmentation.18b The carbon-chloride bond of 16 is then
anti-periplanar to the ring-fusion carbon-carbon bond allowing for
a concerted 1,2-migration to generate an azulenium carbocation 18.
Elimination of the newly formed bridgehead methine affords the
diene 19 which undergoes a 1,5-hydride shift to form the more
MClx
Yield
Ratio
4 (
a
)
8 (
b)
9
ZnCl2
SnCl4
CuCl
100%
100%
100%
100%
0
0
0
0
100
100
100
0
0
0
0
100
PdCl2
2.3. Rearrangement reactions
The initial instability of the isolated alcohol 4 was thought to be
due to an acid catalysed elimination of water to potentially give the
alkene 11. To investigate this hypothesis, the alcohol 4 was treated
with montmorillonite K10 in anhydrous dichloromethane
(Scheme 4). A single product was formed in 80% yield that was not
the alkene 11. The product was identified as the ketone 12. The IR
spectrum indicated the OH stretch in 4 at 3510 cmꢀ1 was replaced
by a new carbonyl absorbance at 1705 cmꢀ1. The presence of a ke-
tone was confirmed by a resonance at 210.0 ppm in the 13C NMR
spectrum. In the 1H NMR spectrum, the resonance due to H3 was
absent. There was also an upfield shift of the H18 methyl protons to
1.12 ppm which suggested that the methyl group was not allylic.
From 2D NMR experiments the C18 and C19 methyl groups were
both attached to C4, reminiscent of the labdane diterpenes. There
are few examples of such rearrangements, which is effectively
a partial reversal of the labdane to clerodane rearrangement. A
number of related rearrangements have been reported including
the total synthesis of (þ)-aureol, the rearrangement of hopenes
stable diene 17. Based on this mechanism the epimeric b-alcohol 8
should give different products, as the chloride substituent is axial
and would preferentially undergo a C19 methyl shift. Identical re-
action conditions were applied to the
b-alcohol 8 (Scheme 6). As
predicted the diene 17 was not observed, but a 1:1 mixture of two
Scheme 4. Acid mediated rearrangement of 4 with montmorillonite K10.
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V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
5
Table 3
Synthetic route to enone 26
inseparable compounds was isolated. The structures were tenta-
tively assigned as the epimers 20. The 1H NMR spectrum of the
mixture contained two vinylic signals at 5.15 and 5.51 ppm, four
allylic methyl and four aliphatic methyl signals.
Conditions
Yield
27, DDQ (4 equiv), sym-collidine (2 equiv), CH2Cl2, RT, o/n
27, DDQ (4 equiv), sym-collidine (2 equiv), MeCN, RT, 5 h
28, DDQ (2 equiv), sym-collidine (1 equiv), MeCN, RT, o/n
28, DDQ (4 equiv), sym-collidine (2 equiv), CH2Cl2, RT, o/n
45%
47%
47%
53%
Scheme 5. PCl5 mediated rearrangement of 4.
due to hydrolysis back to the ketone 7. Key signals for 21 were
found in the 1H NMR spectrum at 2.40 (3H, s), 7.27 (2H, d) and
7.82 ppm (2H, d) associated with the tosyl hydrazone. The oxime 22
was synthesised upon addition of hydroxylamine hydrochloride
and sodium acetate in water with a yield of 58% (Scheme 7). This
yield was improved to 79% when hydroxylamine hydrochloride and
pyridine were used. The O-methyl 23 and O-benzyl oximes 24 were
synthesised using similar conditions in yields of 89% and 76%, re-
spectively. All three oximes had an (E)-orientation based on an NOE
correlation between the substituents and H7. CeH activation of the
O-methyl oxime 23 was attempted by using conditions published
by Sanford and co-workers to form the acetoxy product 25,19
though all attempts were unsuccessful since PhI(OAc)2 reacted
with the C3 alkene of 23.20
Scheme 6. Proposed products of the PCl5-mediated rearrangement of 8.
2.4. Further Reactions
The dehydrogenated product 26 allows for the complete func-
Condensation reactions of the C6 ketone 7 were studied to in-
troduce nitrogen into the molecule. Oximes and hydrazones were
formed under standard conditions (Scheme 7). Treatment of 7 with
tosyl hydrazide in methanol gave the tosyl hydrazone 21 with a 91%
conversion from starting material by 1H NMR of the isolated ma-
terial. Upon purification, the isolated yield of 21 was reduced to 54%
tionalisation of the
hydrogenation at C7eC8 of 7 to give the
B
ring of the clerodane, however de-
-unsaturated carbonyl
a,b
compound 26 was problematic. When the ketone 7 was reacted
with IBX or IBX$N-oxide reagents (Table 3),21 only small amounts
(<5%) of the enone 26 were observed in the reaction mixture. The
Scheme 7. Compounds synthesised from 7 and the attempted acetoxylation.
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6
V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
low reactivity of 7 toward these two reagents can be attributed to
the steric congestion around H8.21 An alternative two-step pro-
cedure method was used to synthesise the enone 26. The silyl enol
ethers 27 and 28 were prepared by reacting 7 with TBSCl (10 equiv),
NaI (10 equiv) and triethylamine in acetonitrile under strictly an-
hydrous conditions. The outcome of this reaction was variable with
either 27, 28 or a mixture of both 27 and 28 being isolated from the
reaction. The bis silyl enol ether 27 was highly unstable and could
not be purified by chromatography. TBSOTf (5 equiv) and triethyl-
amine (10 equiv) could also be used instead of TBSCl and gave
similar results. A SaegusaeIto oxidation of 27 and 28 was explored
but was ultimately ineffective. Both 27 and 28 were oxidised with
DDQ and sym-collidine22 to afford 26 in 45e53% yield in either
acetonitrile or dichloromethane (Table 3). The key 1H NMR signals
attributed to the enone 26 in CDCl3 were at 5.83 (H7) and 1.98 ppm
(H17), though the signal at 5.83 ppm overlapped with that attrib-
uted to H14. Shifting of the two signals was noted in the 1H NMR
spectrum of 26 when run in d6-acetone (5.74 and 5.90 ppm).
3. Conclusions
Three clerodane diterpenes 4e6 were isolated from the leaf resin
of D. ceratocarpa using a rapid extraction technique. The allylic al-
cohol 5 and the alcohol 4 were unreported compounds. The alcohol 4
was isolated in an appreciable quantity (0.5% w/w of plant) and its
inherent chemistry was investigated. The reduction of the ketone 7
with sodium borohydride and lanthanide salts provided an in-
teresting reversal of the inherent selectivity of the hydride addition.
Two new cationic rearrangements of 4 were observed. Preliminary
studies into the functionalisation of the decalin ring of 4 were con-
ducted with excellent stereoselectivity observed. These results show
that D. ceratocarpa is a viable source of clerodane diterpenes, which
can be selectively functionalised to provide a range of clerodane
derivatives for future evaluation on their medicinal properties.
CCDC-1406905 (for 4), contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.u/data_request/cif.
Finally, the inherent
p-facial selectivity of the C3 alkene in ox-
idation reactions was investigated. A trans-clerodane, kerlinic acid
methyl ester, has shown excellent
p
-facial selectivity in epoxida-
4. Experimental section
4.1. Isolation
tion reactions.23 The reaction of 7 with 1.5 equiv of m-CPBA in
dichloromethane provided the epoxide 29 in 92% yield (Scheme 8)
as a single stereoisomer. An NOE correlation between the C18 and
C19 methyl and the C18 methyl and H3 confirmed that all three
substituents were on the same face, thus epoxidation had occurred
D. ceratocarpa was grown from seedlings on a private property
near Balingup, WA. This plant was collected in October 2011, No-
vember 2012, November 2013 and October 2014. The leaves were
collected and sent the following day to Curtin University. They were
left out for 48e72 h to dry so that any excess moisture was re-
moved. Once the leaves were dry, they were stored at room tem-
perature in a dark room and used accordingly. Leaves of D.
ceratocarpa (200.00 g) were steeped in diethyl ether (1.5 L) for
30 min. The extract was filtered and evaporated under reduced
pressure to give a yellow-green foamy solid (7.45 g, 3.7% w/w,
3.0e4.3% w/w common). A portion of the resin (3.51 g) was then
subjected to flash chromatography on silica gel treated with 1%
triethylamine. Elution with 30% ethyl acetate in petrol to 20%
methanol in ethyl acetate gave compounds 4 (0.98 g, 28% w/w
resin), 5 (0.03 g, 0.9% w/w resin) and 6 (0.12 g, 3.5% w/w resin).
on the top b-face of the molecule. Dihydroxylation of the alkene of 7
was also investigated using Sharpless conditions to determine the
match/mismatch pairing between the two commercial mixes AD-
mix
mixture of the diastereomers 30 and 31 was obtained in 56% yield,
however when AD-mix was used only the diastereoisomer 30 was
a and AD-mixb. When AD-mixa was used, a 1:1 inseparable
b
obtained in 72% yield. Like 29, the stereochemistry of the diol 30
was determined by an NOE correlation between C18 and C19. These
reactions indicate that AD-mix
eoselectivity within 7 whereas AD-mix
b
complements the inherent ster-
competes with it.
a
4.1.1. Alcohol 4. mp 144e146 ꢁC. [
(400 MHz, CDCl3): 5.82e5.78 (1H, m), 5.23 (1H, br s), 4.72 (2H, d,
a]
D
25 e40 (c 0.001, CHCl3). 1H NMR
d
J¼1.7 Hz), 3.53 (1H, dd, J¼11.1, 4.0 Hz), 2.30e2.03 (3H, m), 1.82 (3H,
s), 1.69e1.46 (9H, m), 1.26 (1H, dd, J¼12.2, 2.1 Hz), 1.02 (3H, s), 0.82
(3H, d, J¼5.9 Hz), 0.76 (3H, s). 13C NMR (100 MHz, CDCl3):
d 174.1 (C),
170.9 (C),143.8 (C),122.1 (CH),115.2 (CH), 75.4 (CH), 73.1 (CH2), 45.6
(CH), 44.1 (C), 38.5 (C), 37.7 (CH2), 35.4 (CH2), 34.7 (CH), 26.7 (CH2),
22.4 (CH3), 22.1 (CH2), 18.0 (CH2), 17.7 (CH3), 15.7 (CH3), 15.0 (CH3).
Mp 144e146 ꢁC. IR (film, cmꢀ1): 3510, 2947, 1786, 1743, 1635, 1440.
HRMS (EI) calcd for C20H31O3 (MþH)þ 319.2273, found 319.2276.
4.1.2. Allylic alcohol 5. [
CDCl3):
a]
25 e42 (c 0.07, CHCl3). 1H NMR (400 MHz,
D
d
5.84e5.81 (1H, m), 5.59 (1H, dd, J¼4.5, 2.5 Hz), 4.73 (2H, d,
J¼1.6 Hz), 4.28 (1H, d, J¼12.0 Hz), 4.03 (1H, d, J¼12.0 Hz), 3.71e3.62
(1H, m), 2.56 (2H, br s), 2.30e2.11 (3H, m), 2.10e1.96 (1H, m),
1.70e1.50 (7H, m),1.41 (1H, t, J¼7.3 Hz),1.29 (1H, dd, J¼12.0,1.9 Hz),
1.10 (3H, s), 0.85 (3H, d, J¼5.8 Hz), 0.78 (3H, s). 13C NMR (100 MHz,
CDCl3):
d 170.8 (C), 146.1 (C), 128.3 (CH), 115.3 (CH), 75.1 (CH), 73.2
(CH2), 66.8 (CH2), 60.5 (C), 45.6 (CH), 44.3 (C), 38.5 (C), 36.3 (CH2),
35.5 (CH2), 34.9 (CH), 26.7 (CH2), 22.2 (CH2), 18.1 (CH3), 17.9 (CH2),
16.4 (CH3), 15.7 (CH3). IR (film, cmꢀ1): 3354, 2927, 2874, 1779, 1738,
1636, 1449, 1172, 1016. HRMS (EI) calcd for C20H29O4 (MꢀH)þ
333.2060, found 333.2058.
4.1.3. Furan 6. 1H NMR (400 MHz, CDCl3):
7.21e7.18 (1H, m), 6.25 (1H, dd, J¼1.7, 0.9 Hz), 5.24 (1H, br s), 3.57
d
7.34 (1H, t, J¼1.7 Hz),
Scheme 8. Epoxidation and dihydroxylation reactions.
Please cite this article in press as: Moussa, V. N.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.062

V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
7
(1H, dd, J¼11.1, 4.9 Hz), 2.32e2.14 (2H, m), 2.10e1.99 (2H, m),
1.86e1.83 (3H, m), 1.74e1.66 (2H, m), 1.66e1.59 (3H, m), 1.55e1.49
(2H, m), 1.39 (1H, d, J¼2.4 Hz), 1.36 (1H, d, J¼2.4 Hz), 1.03 (3H, s),
0.85 (3H, d, J¼6.7 Hz), 0.73 (3H, s). 13C NMR (100 MHz, CDCl3):
then water (2ꢂ20 mL). The organic phase was dried (MgSO4) and
concentrated in vacuo to afford the ketone 7 as a white solid
(24 mg, 83%). All spectral data were identical to 7 synthesised from
the a-alcohol 4 described previously.
d
143.9 (C), 142.9 (CH), 138.5 (CH), 125.7 (C), 122.4 (CH), 111.1 (CH),
75.8 (CH), 45.7 (CH), 44.2 (C), 38.7 (C), 38.6 (CH2), 38.0 (CH2), 34.7
(CH), 26.8 (CH2), 22.5 (CH3), 18.1 (CH2), 18.0 (CH2), 17.9 (CH3), 15.8
(CH3), 15.1 (CH3). Spectral data for this compound matched that
provided in literature.10
4.5. Reduction of 7 under Luche conditionsdgeneral method
The LnCl3$xH2O (Ln¼La/Ce/Sm/Eu/Tb/Yb, 0.063 mmol, 1 equiv)
was dissolved in methanol (0.50 mL) and cooled to ꢀ84 ꢁC. With
stirring, the ketone 7 (20 mg, 0.063 mmol,1 equiv) was added. After
a few minutes of stirring, sodium borohydride (2.4 mg, 0.063 mmol,
1 equiv) was added to the reaction in one portion and the reaction
continued stirring at ꢀ84 ꢁC for 3 h. The reaction mixture was
concentrated and the residue was dissolved with dichloromethane
(20 mL). The organic phase was washed with water (4ꢂ20 mL),
dried (CaCl2) and concentrated under reduced pressure to afford
a colourless residue containing a mixture of compounds 4 and 8
(98e100%).
4.2. Oxidation of 4
PCC (270 mg, 1.23 mmol, 1.5 equiv) was added to a solution of
the alcohol 4 (260 mg, 0.82 mmol, 1 equiv) in dichloromethane
(10 mL) and the mixture was stirred at room temperature under
a nitrogen atmosphere. After 8 h, the reaction was diluted with
dichloromethane (50 mL) and filtered through a plug of FlorisilÒ.
The filtrate was washed with 1 M sodium hydroxide (2ꢂ50 mL) and
water (4ꢂ50 mL). After drying over MgSO4, the solution was con-
centrated under reduced pressure to give 7 as a pale yellow oil
4.6. Reduction of 7 with MClxdgeneral method
25
which crystallised to a solid (261 mg, 99%), mp 118e120 ꢁC. [
a]
D
e147 (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3):
d
5.85e5.82 (1H,
The chosen MClx (M¼Zn2þ/Sn4þ/Cuþ, 0.063 mmol, 1 equiv) was
dissolved in methanol (0.50 mL) and cooled to ꢀ84 ꢁC. With stir-
ring, the ketone 7 (20 mg, 0.063 mmol, 1 equiv) was added. Once
the solution had stirred for a few minutes, sodium borohydride
(2.4 mg, 0.063 mmol, 1 equiv) was added to the reaction in one
portion. Stirring was continued at ꢀ84 ꢁC for 3 h before the solvent
was removed in vacuo. Dichloromethane (20 mL) was added to
dissolve the residue and this was washed with water (4ꢂ20 mL),
dried (CaCl2) and concentrated under reduced pressure to afford 8
as a colourless oil (20 mg, 100%). The characterisation data for 8
matched that provided previously.
m), 5.40e5.36 (1H, m), 4.71 (2H, d, J¼1.7 Hz), 2.83 (1H, dd, J¼13.1,
12.3 Hz), 2.22e2.16 (1H, m), 2.13 (1H, dd, J¼12.3, 4.8 Hz), 2.06 (2H,
dd, J¼12.3, 4.0 Hz), 2.02e1.92 (2H, m), 1.81 (3H, dt, J¼2.5, 1.3 Hz),
1.72 (1H, ddd, J¼14.4, 12.3, 4.8 Hz), 1.63 (3H, t, J¼4.0 Hz), 1.60e1.56
(1H, m), 1.42 (3H, s), 1.02 (3H, s), 0.94 (3H, d, J¼6.7 Hz). 13C NMR
(100 MHz, CDCl3):
d 214.3 (C), 174.0 (C), 170.2 (C), 139.5 (C), 123.8
(CH), 115.6 (CH), 73.2 (CH2), 55.4 (C), 50.8 (CH), 43.7 (CH2), 41.5
(CH), 39.4 (C), 35.8 (CH2), 26.8 (CH2), 22.3 (CH2), 20.2 (CH3), 19.9
(CH3), 18.64 (CH3), 18.59 (CH2), 16.4 (CH3). IR (film, cmꢀ1): 2951,
1786, 1755, 1702, 1638, 1436. HRMS (EI) calcd for C20H29O3 (MþH)þ
317.2117, found 317.2112.
4.7. Conjugate reduction of 7 to form 9
4.3. Reduction of 7
A stirred solution of PdCl2 (11 mg, 0.063 mmol, 1 equiv) in
methanol (0.50 mL) was cooled to ꢀ84 ꢁC under nitrogen. The
ketone 7 (20 mg, 0.063 mg, 1 equiv) was added to the reaction
mixture, followed by sodium borohydride (2.4 mg, 0.063 mmol,
1 equiv) a few minutes later. The resulting solution was stirred at
ꢀ84 ꢁC for 3 h. The reaction mixture was concentrated under re-
duced pressure and the residue was dissolved in dichloromethane
(20 mL). The solution was washed with water (5ꢂ20 mL), dried
(CaCl2) and concentrated under reduced pressure to provide 9 as
A stirred solution of the ketone 7 (40 mg, 0.126 mmol,1 equiv) in
methanol (0.50 mL) was cooled to ꢀ84 ꢁC under nitrogen. Sodium
borohydride (5 mg, 0.126 mmol, 1 equiv) was added and the mix-
ture continued stirring at ꢀ84 ꢁC for 3 h. The reaction mixture was
concentrated and the residue was dissolved with dichloromethane
(20 mL). The organic phase was washed with water (4ꢂ20 mL),
dried (CaCl2) and concentrated under reduced pressure to afford
a clear residue. Radial chromatography (1% triethylamine treated
silica, 15% ethyl acetate in petrol to 50% ethyl acetate) gave 8 as
a colourless oil (25 mg, 100%) without the need for further purifi-
25
24
a colourless oil (36 mg, 90%). [
a
]
e114 (c 0.006, CHCl3). 1H NMR
cation. [
a
]
D
e52 (c 0.004, CHCl3). 1H NMR (400 MHz, CDCl3):
D
(400 MHz, CDCl3):
d
5.85e5.82 (1H, m), 5.46e5.42 (1H, m), 4.73
d
5.45e5.41 (1H, m), 4.43 (1H, ddd, J¼9.0, 7.5, 1.6 Hz), 3.88 (1H, dd,
(2H, d, J¼1.2 Hz), 3.86 (1H, t, J¼2.8 Hz), 2.36 (1H, ddd, J¼16.3, 12.3,
3.8 Hz), 2.23 (1H, ddd, J¼16.3, 12.3, 4.6 Hz), 2.07e2.01 (2H, m),
1.84e1.80 (1H, m), 1.77e1.65 (2H, m), 1.73e1.70 (3H, m), 1.60e1.48
(6H, m), 1.04 (3H, s), 0.81 (3H, d, J¼6.9 Hz), 0.78 (3H, s). 13C NMR
J¼9.0, 7.5 Hz), 3.85e3.82 (1H, m), 2.63 (1H, ddd, J¼17.2, 8.4, 1.6 Hz),
2.50e2.39 (1H, m), 2.14 (1H, ddd, J¼17.2, 8.4, 1.6 Hz), 2.06e1.98 (3H,
m), 1.79e1.66 (2H, m), 1.72e1.70 (3H, dt, J¼2.2, 1.6 Hz), 1.54e1.38
(5H, m), 1.30e1.24 (3H, m), 1.02 (3H, s), 0.79 (3H, dd, J¼6.9, 1.6 Hz),
(100 MHz, CDCl3):
d
174.2 (C), 171.2 (C), 140.6 (C), 125.3 (CH), 115.2
0.73 (3H, s). 13C NMR (100 MHz, CDCl3):
d 177.2 (C), 140.7 (C), 125.4
(CH), 73.7 (CH2), 71.3 (CH), 43.8 (C), 39.1 (CH), 38.6 (C), 35.6 (CH2),
33.7 (CH2), 28.9 (CH), 27.0 (CH2), 22.5 (CH2), 20.5 (CH3), 18.2 (CH3),
18.0 (CH2), 17.6 (CH3), 15.7 (CH3). IR (film, cmꢀ1): 3478, 2954, 2929,
1779, 1745, 1636, 1448, 1386, 1171, 1024. HRMS (EI) calcd for
(CH), 73.6 (CH2), 71.4 (CH), 43.7 (C), 39.1 (CH), 38.4 (C), 36.5 (CH),
36.2 (CH2), 34.8 (CH2), 33.7 (CH2), 28.8 (CH), 27.0 (CH2), 26.8 (CH2),
20.6 (CH3), 18.3 (CH3), 18.1 (CH2), 17.6 (CH3), 15.7 (CH3). IR (film,
cmꢀ1): 3496, 2927, 1774, 1454, 1385, 1170, 1017. HRMS (EI) calcd for
C
20H31O3 (MþH)þ 319.2273, found 319.2274.
C
20H32O3Na (MþNa)þ 343.2249, found 343.2249.
4.4. Oxidation of the
b-alcohol 8
4.8. Synthesis of the triol 10
The -alcohol 8 (29 mg, 0.091 mmol, 1 equiv) was dissolved in
b
A stirred solution of the alcohol 4 (29 mg, 0.091 mmol, 1 equiv)
in dry tetrahydrofuran (2 mL) was cooled to 0 ꢁC under nitrogen.
Lithium aluminium hydride (10 mg, 0.273 mmol, 3 equiv) was
added and the reaction continued to stir for a day at room tem-
perature. Aqueous sodium hydroxide (3 M, 5 mL) was added to the
mixture and stirring continued for 10 min. The aqueous phase was
dichloromethane (5 mL) under nitrogen. PCC (30 mg, 0.136 mmol,
1.5 equiv) was added to the mixture, and stirring was continued
overnight at room temperature. The solution was diluted with
dichloromethane (20 mL) and filtered through a plug of FlorisilÒ.
The filtrate was washed with 1 M sodium hydroxide (2ꢂ20 mL),
Please cite this article in press as: Moussa, V. N.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.062

8
V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
removed and the organic phase was washed with water (2ꢂ20 mL),
16.5 (CH3), 15.1 (CH3). IR (film, cmꢀ1): 2956, 2921, 2869, 2852, 1779,
1747, 1638, 1448, 1169, 1128, 1030. HRMS (EI) calcd for C20H29O2
(MþH)þ 301.2168, found 301.2172.
then dried over MgSO4. Concentration in vacuo afforded a colour-
less oil attributed to 10 (25 mg, 85%) as a mixture of di-
25
astereoisomers. [
CDCl3):
a
]
e10 (c 0.0012, CHCl3). 1H NMR (400 MHz,
D
d
5.22 (1H, s), 3.78e3.67 (2H, m), 3.64 (1H, dt, J¼11.5,
4.11. Preparation of the PCl5 rearrangement products 20
3.0 Hz), 3.53 (1H, dd, J¼11.1, 4.7 Hz), 3.49e3.46 (1H, m), 2.04e1.93
(4H, m), 1.87e1.84 (1H, m), 1.84e1.81 (3H, m), 1.74e1.65 (1H, m),
1.61e1.51 (5H, m), 1.50e1.45 (1H, m), 1.43 (1H, s),1.40e1.32 (1H, m),
1.31e1.24 (2H, m), 1.23e1.04 (2H, m), 1.00 (3H, s), 0.80 (3H, dd,
Phosphorus pentachloride (13 mg, 0.061 mmol, 1.3 equiv) and
anhydrous sodium carbonate (5 mg, 0.047 mmol, 1 equiv) were
added to a stirred solution of the b-alcohol 8 (15 mg, 0.047 mmol,
J¼6.6, 1.3 Hz), 0.69 (3H, s). 13C NMR (100 MHz, CDCl3)
d
143.93 (C),
1 equiv) in dry dichloromethane (1 mL) at 0 ꢁC. The reaction was
stirred under nitrogen at 0 ꢁC for 30 min and then warmed to room
temperature for 3 h. The reaction mixture was diluted with
dichloromethane (20 mL) and washed with water (3ꢂ20 mL). The
organic phase was dried (CaCl2) and concentrated in vacuo to leave
a yellow oil. Radial chromatography (1% triethylamine treated sil-
ica, 100% petrol) afforded a colourless oil (15 mg, 95%) containing
a 1:1 mixture of two compounds tentatively assigned as 20. 1H
143.87 (C), 122.43 (CH), 122.36 (CH), 75.8 (CH), 66.56 (CH2), 66.52
(CH2), 61.3 (CH2), 45.52 (CH), 45.49 (CH), 44.1 (C), 40.10 (CH), 40.08
(CH), 38.4 (C), 38.0 (CH2), 35.94 (CH2), 35.85 (CH2), 35.77 (CH2),
35.73 (CH2), 34.55 (CH), 34.51 (CH), 26.8 (CH2), 24.46 (CH2), 24.40
(CH2), 22.5 (CH3), 18.07 (CH3), 18.02 (CH2), 18.00 (CH2), 15.8 (CH3),
15.1 (CH3). IR (film, cmꢀ1): 3344, 2922, 2873, 1446, 1383, 1080, 998.
HRMS (EI): a molecular ion could not be found.
NMR (400 MHz, CDCl3): d 5.86e5.84 (2H, m), 5.51 (1H, s), 5.15 (1H,
4.9. Preparation of the montmorillonite K10 rearrangement
product 12
s), 4.76e4.73 (4H, m), 2.38e2.29 (4H, m), 2.21e2.09 (4H, m),
2.00e1.98 (3H, m), 1.98e1.96 (3H, dd, J¼2.2, 1.4 Hz), 1.95e1.89 (3H,
m), 1.82 (6H, br s), 1.80e1.69 (6H, m), 1.63 (7H, m), 0.86 (3H, d,
J¼7.2 Hz), 0.83 (3H, d, J¼6.7 Hz), 0.65 (3H, s), 0.56 (3H, s). 13C NMR
Activated montmorillonite K1024 (15 mg) was added to a solu-
tion of the alcohol 4 (10 mg, 0.031 mmol, 1 equiv) in dry
dichloromethane (0.50 mL) under a nitrogen atmosphere. The so-
lution was stirred at room temperature for 1 day, then heated at
reflux for 1 week. The reaction mixture was filtered and diluted
with dichloromethane (10 mL). The solution was washed with
water (20 mL) and back-extracted with dichloromethane (5 mL).
The organic phases were combined, dried (CaCl2) and concentrated
in vacuo to leave a yellow oil. Radial chromatography (20% ethyl
(100 MHz, CDCl3):
d
174.2 (2ꢂC), 171.3 (C), 171.2 (C), 134.4 (C), 132.9
(C), 132.4 (C), 131.8 (CH), 131.1 (C), 130.5 (C), 128.5 (C), 127.5 (CH),
115.22 (CH), 115.18 (CH), 73.2 (2ꢂCH2), 43.3 (CH), 42.8 (CH), 41.1
(CH2), 39.0 (C), 37.3 (CH), 36.8 (C), 35.1 (CH2), 33.7 (CH2), 33.4 (CH2),
33.2 (CH), 27.3 (CH2), 25.6 (CH3), 24.9 (CH3), 24.4 (CH2), 24.3 (CH2),
22.9 (CH3), 22.6 (CH2), 22.5 (CH3), 22.4 (CH2), 22.2 (CH2), 15.7 (CH3),
15.14 (CH3), 15.13 (CH3), 14.7 (CH3).
acetate in petrol to 40% ethyl acetate) gave the rearrangement
4.12. Preparation of the tosyl hydrazone 21
24
product 12 as a pale yellow oil (8 mg, 80%). [
a
]
e6.1 (c 0.002,
D
CHCl3). 1H NMR (400 MHz, CDCl3):
d
5.88e5.85 (1H, m), 4.75 (2H, d,
A solution of the ketone 7 (17 mg, 0.05 mmol, 1 equiv) and tosyl
hydrazide (15 mg, 0.08 mmol, 1.5 equiv) in methanol (1 mL) was
heated to 50e60 ꢁC under nitrogen. After 2 days, the solution was
concentrated under reduced pressure, and the residue was dis-
solved in dichloromethane (20 mL). The mixture was washed with
1 M hydrochloric acid (20 mL), followed by water (2ꢂ20 mL). The
organic phase was dried (CaCl2) and concentrated in vacuo to give
a colourless oil. Radial chromatography (20% ethyl acetate in petrol
to 50% ethyl acetate) provided 21 as a colourless oil (14 mg, 54%). 1H
J¼1.7 Hz), 2.32 (1H, dd, J¼13.6, 1.0 Hz), 2.27e2.22 (2H, m), 2.13 (1H,
dd, J¼13.6, 3.8 Hz), 2.04 (1H, s), 2.01e1.98 (1H, m), 1.84 (1H, ddd,
J¼13.6, 6.5, 3.8 Hz), 1.73e1.69 (1H, m), 1.68 (1H, d, J¼1.0 Hz), 1.64
(2H, dd, J¼9.8, 6.5 Hz), 1.40 (1H, dt, J¼13.6, 3.3 Hz), 1.33e1.28 (2H,
m),1.20 (1H, dd, J¼12.6, 4.2 Hz),1.12 (3H, s),1.07 (3H, s), 0.97 (3H, s),
0.88 (3H, d, J¼6.8 Hz). 13C NMR (100 MHz, CDCl3):
d 210.0 (C), 173.9
(C), 170.2 (C), 115.5 (CH), 73.2 (CH2), 57.8 (CH), 47.8 (CH2), 43.2
(CH2), 43.1 (CH), 38.8 (C), 37.7 (CH), 33.7 (CH2), 32.9 (C), 31.0 (CH3),
29.9 (CH2), 27.3 (CH2), 21.5 (CH2), 20.3 (CH3), 15.9 (CH3), 15.1 (CH3).
IR (film, cmꢀ1): 2926, 2871, 2860, 1779, 1749, 1706, 1639, 1457.
HRMS (ESI) calcd for C20H31O3 (MþH)þ 319.2273, found 319.2273.
NMR (400 MHz, CDCl3):
d
7.82 (2H, d, J¼8.1 Hz), 7.58 (1H, s), 7.27
(2H, d, J¼8.1 Hz), 5.81e5.77 (1H, m), 5.32 (1H, d, J¼5.3 Hz),
4.70e4.64 (2H, m), 2.42e2.38 (2H, m), 2.40 (3H, s), 2.05 (2H, t,
J¼13.4 Hz), 2.00e1.86 (3H, m), 1.64e1.61 (3H, m), 1.58 (2H, dd,
J¼12.2, 5.3 Hz), 1.50e1.40 (3H, m), 1.31 (1H, dd, J¼10.7, 2.8 Hz), 1.23
(3H, s), 0.88 (3H, d, J¼6.7 Hz), 0.86 (3H, s). Further characterisation
could not be completed due to hydrolysis back to 7.
4.10. Preparation of the PCl5 rearrangement product 17
A stirred solution of the alcohol 4 (32 mg, 0.10 mmol, 1 equiv) in
freshly dried dichloromethane (1 mL) was cooled to 0 ꢁC under
nitrogen. Anhydrous sodium carbonate (0.011 g, 0.100 mmol,
4.13. Preparation of the oxime 22
1
equiv) was added, followed by phosphorus pentachloride
(0.028 g, 0.131 mmol, 1.3 equiv). The reaction was warmed to room
temperature overnight, then diluted with dichloromethane
(10 mL). The reaction mixture was washed with water (3ꢂ10 mL),
the organic extract was dried (CaCl2) then concentrated under re-
duced pressure to yield a yellow residue. Radial chromatography
A stirred solution of the ketone 7 (22 mg, 0.07 mmol, 1 equiv),
CaCl2 (w50 mg) and hydroxylamine hydrochloride (7.2 mg,
0.10 mmol, 1.5 equiv) in pyridine (1 mL) was heated to 50 ꢁC for 2
days. The reaction mixture was cooled and diethyl ether (20 mL)
was added. The organic phase was washed with 1 M hydrochloric
acid (2ꢂ20 mL), 10% sodium bicarbonate solution (2ꢂ20 mL), water
(2ꢂ20 mL) and brine (20 mL). The organic phase was dried and
concentrated under reduced pressure to afford the oxime 22 as
a colourless oil (18 mg, 79%) without the need for further purifi-
(100% petrol to 10% ethyl acetate in petrol) afforded 17 as a col-
24
ourless oil (17 mg, 57%). [
a
]
e18 (c 0.002, CHCl3). 1H NMR
D
(400 MHz, CDCl3):
d
5.85e5.82 (1H, m), 4.73 (2H, d, J¼1.7 Hz),
2.53e2.44 (1H, m), 2.43e2.34 (1H, m), 2.31e2.17 (2H, m), 2.06e1.98
(3H, m), 1.97e1.87 (3H, m), 1.83 (2H, d, J¼0.8 Hz),1.80e1.75 (1H, m),
1.73 (1H, m), 1.67 (2H, q, J¼0.8 Hz), 1.62 (2H, d), 1.04 (1H, dd, J¼6.9,
4.7 Hz), 0.96 (3H, d, J¼6.9 Hz), 0.85 (3H, s). 13C NMR (100 MHz,
cation. [a] d 7.10
26 e174 (c 0.015, CHCl3). 1H NMR (400 MHz, CDCl3):
D
(1H, s), 5.83e5.81 (1H, m), 5.45e5.41 (1H, m), 4.70 (2H, d, J¼1.7 Hz),
3.19 (1H, dd, J¼12.6, 3.6 Hz), 2.27e2.16 (1H, m), 2.15e2.08 (1H, m),
2.06e1.95 (2H, m),1.86 (1H, t, J¼12.6 Hz),1.80 (3H, dt, J¼2.4,1.3 Hz),
1.77e1.66 (3H, m), 1.58e1.53 (1H, m), 1.53e1.49 (2H, dd, J¼6.6,
3.6 Hz), 1.32 (3H, s), 0.95 (3H, d, J¼6.6 Hz), 0.92 (3H, s). 13C NMR
CDCl3): d 174.3 (C), 171.5 (C), 144.7 (C), 138.9 (C), 134.8 (C), 127.5 (C),
115.1 (CH), 73.3 (CH2), 52.0 (C), 40.9 (CH2), 37.6 (CH), 35.4 (CH2),
34.9 (CH2), 33.7 (CH2), 29.9 (CH2), 24.7 (CH2), 20.9 (CH3), 20.7 (CH3),
Please cite this article in press as: Moussa, V. N.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.062

V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
9
(100 MHz, CDCl3):
d
174.0 (C), 170.5 (C), 165.6 (C), 140.1 (C), 124.0
1.26 mmol, 10 equiv) was added in one portion to the reaction
mixture. Stirring was continued at room temperature. After 3 days,
the reaction mixture was diluted with petrol (20 mL) and stirred for
5 min. The organic phase was washed with water (4ꢂ20 mL), dried
(CaCl2) then concentrated under reduced pressure to afford a col-
ourless residue. Radial chromatography (1% triethylamine treated
silica, petrol) provided the di-TBS ether 27 as a colourless oil
(CH), 115.3 (CH), 73.1 (CH2), 52.1 (CH), 48.2 (C), 39.5 (C), 38.9 (CH3),
35.7 (CH2), 30.5 (CH), 27.1 (CH2), 26.0 (CH2), 22.4 (CH2), 20.0 (CH3),
18.75 (CH3), 18.69 (CH3), 16.2 (CH3). IR (film, cmꢀ1): 3374, 2957,
2929, 1780, 1744, 1636, 1444, 930, 730. HRMS (ESI) calcd for
C
20H30NO3 (MþH)þ 332.2226, found 332.2221.
4.14. Preparation of the O-methyl oxime 23
(29 mg, 43%). [
a
]
25 þ33 (c 0.01, CHCl3). 1H NMR (400 MHz, CDCl3):
D
d
6.59 (1H, d, J¼1.2 Hz), 5.11e5.07 (1H, m), 4.99 (1H, d, J¼1.2 Hz),
Methoxyamine hydrochloride (22 mg, 0.27 mmol, 1.3 equiv) was
added in one portion to a solution of the ketone 7 (65 mg,
0.21 mmol, 1 equiv) in pyridine (2 mL) under nitrogen. The reaction
was stirred at 50 ꢁC for 20 h. The reaction mixture was cooled to
room temperature before diethyl ether (100 mL) was added. The
solution was washed with 1 M hydrochloric acid (2ꢂ50 mL), 10%
sodium bicarbonate solution (1ꢂ50 mL) and water (1ꢂ50 mL). The
4.43 (1H, d, J¼1.6 Hz), 2.43 (1H, qd, J¼7.2, 1.6 Hz), 2.28e2.20 (1H,
m), 2.17e2.09 (3H, m), 1.86e1.83 (3H, m), 1.70e1.56 (3H, m), 1.50
(2H, m), 1.15 (3H, s), 0.96 (9H, s), 0.95 (9H, s), 0.84 (3H, d, J¼7.2 Hz),
0.70 (3H, s), 0.23 (6H, s), 0.21 (3H, s), 0.17 (3H, s). 13C NMR
(100 MHz, CDCl3):
d 156.8 (C), 153.5 (C), 146.0 (C), 127.74 (CH),
127.42 (C), 120.6 (CH), 108.9 (CH), 85.2 (CH), 46.6 (CH), 44.3 (C),
37.47 (CH2), 37.42 (C), 35.4 (CH), 26.2 (CH3), 25.6 (CH3), 25.0 (CH2),
23.3 (CH3), 21.2 (CH3), 19.1 (CH2), 18.6 (C), 18.2 (C), 17.9 (CH3), 17.0
(CH2),16.1 (CH3), e3.4 (CH3), e4.6 (CH3), e5.1 (CH3). IR (film, cmꢀ1):
2957, 2930, 2858, 1781, 1751, 1624, 1472, 1255, 1211, 1160, 1090, 838,
778. HRMS (ESI): a molecular ion could not be found.
Compound 28: The ketone 7 (0.103 g, 0.326 mmol, 1 equiv) was
dissolved in freshly dried and distilled acetonitrile (2 mL) and
cooled to 0 ꢁC under nitrogen. Dry sodium iodide (0.49 g,
3.26 mmol, 10 equiv) was added, followed by dry triethylamine
(0.45 mL, 0.33 g, 3.26 mmol, 10 equiv). After 5 min of stirring,
recrystallised TBSCl (0.49 g, 3.26 mmol, 10 equiv) was added in two
portions to the reaction mixture. Stirring was continued and the
reaction was warmed to room temperature over 2 days. Petrol
(20 mL) was added to the reaction mixture and the solution was
washed with water (w10ꢂ20 mL), dried (CaCl2), then concentrated
under reduced pressure to leave a yellow/orange oil. Radial chro-
matography (1% triethylamine treated silica, petrol) afforded the
mono-TBS ether 28 as a colourless oil (90 mg, 64%). 1H NMR
organic phase was dried over MgSO4 and concentrated under re-
25
duced pressure to furnish 23 as a colourless oil (63 mg, 89%). [
a]
D
e210 (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3):
d
5.83e5.79 (1H,
m), 5.41e5.36 (1H, m), 4.70 (2H, d, J¼1.7 Hz), 3.83 (3H, s), 3.09 (1H,
dd, J¼12.9, 3.7 Hz), 2.27e2.11 (2H, m), 2.10e2.01 (2H, m), 1.86 (3H,
dt, J¼2.3,1.3 Hz),1.80 (1H, d, J¼12.9 Hz),1.70e1.64 (2H, m),1.62 (1H,
d, J¼5.2 Hz), 1.55 (1H, d, J¼4.6 Hz), 1.52e1.46 (4H, m), 1.29 (3H, s),
0.92 (3H, d, J¼6.6 Hz), 0.90 (3H, s). 13C NMR (100 MHz, CDCl3):
d
173.9 (C), 170.7 (C), 163.9 (C), 140.4 (C), 123.5 (CH), 115.0 (CH), 73.1
(CH2), 61.2 (CH3), 51.4 (CH), 47.7 (C), 39.3 (C), 38.7 (CH), 35.5 (CH2),
26.8 (CH2), 26.4 (CH2), 22.3 (CH2), 20.14 (CH3), 20.08 (CH3), 18.54
(CH2), 18.50 (CH3), 16.0 (CH3). IR (film, cmꢀ1): 2954, 2936, 1779,
1745, 1637, 1045. HRMS (EI) calcd for C21H32NO3 (MþH)þ 346.2382,
found 346.2387.
4.15. Preparation of the O-benzyl oxime 24
O-Benzylhydroxylamine hydrochloride (35 mg, 0.218 mmol,
1.3 equiv) was added to a solution of the ketone 7 (53 mg,
0.167 mmol, 1 equiv) in pyridine (1 mL) under nitrogen. The re-
action mixture was stirred at 50 ꢁC in an oil bath for 1 day and
allowed to cool to room temperature. The reaction mixture was
diluted with diethyl ether (20 mL) and washed with 1 M hydro-
chloric acid (2ꢂ20 mL), 10% sodium bicarbonate (1ꢂ20 mL) and
water (3ꢂ20 mL). The organic phase was dried (MgSO4) and con-
centrated under reduced pressure to afford a colourless oil. Radial
chromatography (1% triethylamine treated silica, 10% ethyl acetate
(400 MHz, CDCl3): d 5.85e5.82 (1H, m), 5.11e5.07 (1H, m), 4.73 (2H,
d, J¼1.7 Hz), 4.41 (1H, d, J¼1.7 Hz), 2.35 (1H, dd, J¼7.2, 1.7 Hz),
2.30e2.24 (1H, m), 2.22e2.20 (1H, m), 2.18e2.02 (2H, m), 1.85e1.81
(3H, m), 1.76 (1H, s), 1.74e1.65 (1H, m), 1.63 (1H, d, J¼4.4 Hz), 1.59
(1H, dd, J¼9.0, 5.1 Hz), 1.55e1.52 (1H, m), 1.15 (3H, s), 0.95 (9H, s),
0.84 (3H, d, J¼7.2 Hz), 0.74 (3H, s), 0.21 (3H, s), 0.17 (3H, s). 13C NMR
(100 MHz, CDCl3):
d 174.1 (C), 171.0 (C), 153.6 (C), 146.0 (C), 120.4
(CH), 115.2 (CH), 108.1 (CH), 73.2 (CH2), 46.5 (CH), 44.3 (C), 37.3 (C),
35.4 (CH), 34.8 (CH2), 26.1 (CH3), 24.8 (CH2), 23.2 (CH3), 22.3 (CH2),
21.0 (CH3), 18.5 (C), 17.7 (CH3), 17.1 (CH2), 16.1 (CH3), e3.4 (CH3),
e5.1 (CH3). IR (film, cmꢀ1): 2957, 2930, 2858, 1780, 1750, 1639,
1253, 1212, 1159, 1071, 1031, 837, 778. HRMS (EI) calcd for
in petrol to 100% ethyl acetate) gave 24 as a colourless oil (54 mg,
25
76%). [
a]
e144 (c 0.001, CHCl3). 1H NMR (400 MHz, CDCl3):
D
d
7.36e7.27 (5H, m), 5.83e5.80 (1H, m), 5.40e5.35 (1H, m), 5.11 (1H,
C
26H43O3Si (MþH)þ 431.2981, found 431.2990.
d, J¼12.2 Hz), 5.05 (1H, d, J¼12.2 Hz), 4.70 (2H, d, J¼1.7 Hz), 3.17
(1H, dd, J¼12.7, 3.8 Hz), 2.21e2.08 (2H, m), 2.06e2.00 (2H, m),
1.86e1.79 (1H, m), 1.78e1.75 (3H, m), 1.71e1.60 (3H, m), 1.53e1.48
(3H, m), 1.27 (3H, s), 0.90 (3H, d, J¼6.5 Hz), 0.89 (3H, s). 13C NMR
4.17. Synthesis of the di-TBS enol ether 27 with TBSOTf
A solution of the ketone 7 (25 mg, 0.079 mmol, 1 equiv) and
(100 MHz, CDCl3):
d
174.0 (C), 170.7 (C), 164.8 (C), 140.6 (C), 138.8
triethylamine (110
dichloromethane (0.50 mL) was cooled to 0 ꢁC under nitrogen.
TBSOTf (91 L, 104 mg, 0.395 mmol, 5 equiv) was added and the
mL, 80 mg, 0.790 mmol, 10 equiv) in anhydrous
(C), 128.35 (CH), 128.31 (CH), 127.6 (CH), 125.6 (CH), 123.4 (CH),
115.2 (CH), 75.4 (CH2), 73.2 (CH2), 51.6 (CH), 48.0 (C), 39.4 (C), 38.8
(CH), 35.6 (CH2), 30.5 (CH), 26.96 (CH2), 26.86 (CH2), 22.4 (CH2),
20.22 (CH3), 20.17 (CH3), 18.68 (CH2), 18.64 (CH3), 16.2 (CH3). IR
(film, cmꢀ1): 3027, 2956, 2926, 2874, 1779, 1748, 1637, 1454, 1168,
1030. HRMS (EI) calcd for C27H36NO3 (MþH)þ 422.2695, found
422.2704.
m
reaction continued to stir at 0 ꢁC for 30 min. The mixture was di-
luted with dichloromethane (20 mL) and washed with water
(4ꢂ20 mL). The organic phase was dried (CaCl2) and concentrated
in vacuo. A pale yellow solid was obtained, which was subjected to
radial chromatography (100% petrol to 20% ethyl acetate) to afford
the di-TBS ether 27 as a colourless oil (37 mg, 86%). The charac-
terisation data for 27 matched that provided previously.
4.16. Preparation of the silyl enol ethers 27 and 28 with TBSCl
Compound 27: The ketone 7 (40 mg, 0.126 mmol, 1 equiv) was
dissolved in freshly dried and distilled acetonitrile (0.5 mL) under
nitrogen. Dry triethylamine (0.176 mL, 0.126 g, 1.26 mmol, 10 equiv)
was added, followed by dry sodium iodide (0.49 g, 3.26 mmol,
10 equiv). After 5 min of stirring, recrystallised TBSCl (0.191 g,
4.18. Preparation of the enone 26 (method 1)
The di-TBS ether 27 (30 mg, 0.055 mmol, 1 equiv) was dissolved
in dry acetonitrile (3 mL) along with DDQ (50 mg, 0.220 mmol,
4 equiv) and dry sym-collidine (14.5 mL, 0.0110 mmol, 2 equiv). The
Please cite this article in press as: Moussa, V. N.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.062

10
V.N. Moussa et al. / Tetrahedron xxx (2016) 1e11
reaction was stirred under a nitrogen atmosphere at room tem-
perature for 5 h. Water (100 mL) was added and the solution was
extracted with dichloromethane (4ꢂ40 mL). The organic phase was
washed with 5% sodium bicarbonate solution (1ꢂ50 mL) and dried
(MgSO4). The solution was concentration in vacuo to afford an or-
ange solid. Radial chromatography (1% triethylamine treated silica,
petrol to 20% ethyl acetate to 100% ethyl acetate) gave 26 as
introduced in one portion. After 2 days, the reaction was quenched
with sodium sulfite (15 mg) at 0 ꢁC for 30 min. Ethyl acetate (50 mL)
was added and the mixture was washed with water (3ꢂ50 mL),
followed by back-extraction of the combined aqueous phases with
ethyl acetate (20 mL). The organic phases were combined, dried
(MgSO4) and concentrated in vacuo to give a colourless oil. Radial
chromatography (1% triethylamine treated silica, 20% ethyl acetate
a crystalline white solid (8 mg, 47%). [
NMR (400 MHz, CDCl3):
a
]
25 e88 (c 0.001, CHCl3). 1H
in petrol to 100% ethyl acetate) furnished the
b
-diol 30 as a col-
D
25
d
5.85e5.82 (2H, m), 5.46 (1H, d, J¼5.6 Hz),
ourless oil (12 mg, 56%). [
(400 MHz, CDCl3):
(1H, dd, J¼10.8, 4.9 Hz), 3.34 (1H, s), 2.78 (1H, dd, J¼13.5, 12.3 Hz),
2.20 (2H, dd, J¼9.7, 4.9 Hz), 2.03 (1H, dd, J¼12.3, 3.3 Hz), 1.96e1.88
(2H, m), 1.74 (1H, dd, J¼12.3, 5.5 Hz), 1.70 (1H, dd, J¼11.6, 6.1 Hz),
1.62e1.55 (3H, m), 1.53e1.49 (2H, m), 1.46 (3H, s), 1.28 (3H, s), 1.01
a]
e33 (c 0.004, CHCl3). 1H NMR
D
4.68 (2H, d, J¼1.7 Hz), 2.28e2.18 (1H, m), 2.15e2.05 (1H, m), 1.98
(3H, dd, J¼2.4, 1.4 Hz), 1.95 (3H, d, J¼1.4 Hz), 1.90 (1H, dd, J¼13.4,
4.4 Hz), 1.85 (3H, d, J¼1.4 Hz), 1.74e1.69 (1H, m), 1.68e1.59 (3H, m),
d
5.86e5.83 (1H, m), 4.73 (2H, d, J¼1.7 Hz), 3.39
1.33 (3H, s), 1.21 (3H, s). 1H NMR ((CD3)2CO)
d 5.92e5.89 (1H, m),
5.74 (1H, d, J¼1.2 Hz), 5.44e5.37 (1H, m), 4.83 (2H, d, J¼1.7 Hz),
2.46e2.37 (1H, m), 2.03e1.98 (4H, m), 1.95 (3H, m), 1.91 (3H, d,
J¼1.2 Hz), 1.90e1.80 (2H, m), 1.76 (1H, s), 1.65e1.57 (1H, m), 1.31
(3H, s), 0.93 (3H, d, J¼6.8 Hz). 13C NMR (100 MHz, CDCl3)
d 216.6 (C),
173.8 (C), 169.9 (C), 115.6 (CH), 76.2 (C), 73.2 (CH2), 72.4 (CH), 56.9
(C), 44.6 (CH), 43.8 (CH2), 40.4 (CH), 39.2 (C), 35.7 (CH2), 31.7 (CH2),
22.2 (CH2), 21.7 (CH3), 19.9 (CH2), 18.4 (CH3), 16.2 (CH3), 16.0 (CH3).
IR (film, cmꢀ1): 3446, 2926, 2855,1779,1745,1698,1637,1450, 1379,
1131, 1029. HRMS (EI) calcd for C20H31O5 (MþH)þ 351.2172, found
351.2180.
(3H, s),1.23 (3H, s). 13C NMR (100 MHz, CDCl3):
d 203.2 (C),173.8 (C),
169.7 (C), 159.0 (C), 138.3 (C), 128.0 (CH), 124.6 (CH), 115.4 (CH), 73.1
(CH2), 49.9 (C), 43.5 (CH), 42.4 (C), 35.5 (CH2), 26.7 (CH2), 23.7
(CH2), 21.2 (CH3), 20.9 (CH3), 20.7 (CH3), 19.5 (CH2), 19.0 (CH3). IR
(film, cmꢀ1): 2950, 1779, 1744, 1671, 1636, 1440, 1174, 1029. HRMS
(EI) calcd for C20H27O3 (MþH)þ 315.1960, found 315.1966.
4.22. Preparation of the diol mixture 30 and 31
4.19. Preparation of the enone 26 (method 2)
AD-mixa (140 mg) was dissolved in 1:1 tert-butanolewater and
A solution of the mono-TBS ether 28 (31 mg, 0.072 mmol,
1 equiv) in freshly dried dichloromethane (3 mL) was stirred at
room temperature under nitrogen. DDQ (32 mg, 0.140 mmol,
2 equiv) was added in one portion, followed by dry sym-collidine
the phases were mixed for 15 min under nitrogen. The mixture was
cooled to 0 ꢁC and the ketone 6 (23 mg, 0.073 mmol, 1 equiv) was
added in one portion. After 4 days at room temperature, the re-
action was quenched with sodium sulfite (19 mg) at 0 ꢁC for 30 min.
Ethyl acetate (50 mL) was added and the mixture was washed with
water (3ꢂ50 mL), followed by back-extraction of the combined
aqueous phases with ethyl acetate (20 mL). The organic phases
were combined, dried (MgSO4) and concentrated in vacuo to give
(9.5 mL, 0.072 mmol, 1 equiv). After 17 h at room temperature, the
reaction was diluted with dichloromethane (20 mL). The organic
was washed with 5% sodium bicarbonate solution (1ꢂ20 mL), water
(3ꢂ20 mL) and dried (MgSO4). Concentration under reduced
pressure afforded an orange oil. Radial chromatography (1% trie-
thylamine treated silica, petrol to 10% ethyl acetate to 50% ethyl
acetate) provided 26 as a crystalline white solid (12 mg, 53%).
Spectral data of 26 matched that provided previously.
a pale yellow oil containing the a-diol 31 and the b-diol 30 in a 1:1
ratio (18 mg, 72%) as an inseparable mixture.
Acknowledgements
4.20. Epoxidation of 7
VNM would like to acknowledge the Australian Government
and Curtin University for the APA-CUPS scholarship. The authors
acknowledge the facilities, and the scientific and technical assis-
tance of the Australian Microscopy & Microanalysis Research Fa-
cility at the Centre for Microscopy, Characterisation & Analysis, The
University of Western Australia, a facility funded by the University,
State and Commonwealth Governments. VNM and ADP also wish to
thank Dr. Francesco Busetti for MS analysis and Dr. Trevor Payne for
growing and donating D. ceratocarpa.
m-CPBA (20 mg, 0.116 mmol, 1.5 equiv) and sodium bicarbonate
(13 mg, 0.155 mmol, 2 equiv) were added to a solution of the ketone
7 (24 mg, 0.076 mmol, 1 equiv) in dichloromethane (2 mL) under
nitrogen. The reaction was stirred at room temperature for 1.5 h
20% Sodium thiosulfate solution (20 mL) was added to the reaction
mixture and stirred for a further 5 min. The organic phase was
washed with water (2ꢂ50 mL) and dried over MgSO4. Concentra-
tion under reduced pressure provided the epoxide 29 as a colour-
less oil (23 mg, 92%). [
CDCl3):
a]
25 e44 (c 0.005, CHCl3). 1H NMR (400 MHz,
D
Supplementary data
d
5.83e5.80 (1H, m), 4.72 (2H, d, J¼1.7 Hz), 2.77 (1H, d,
J¼4.9 Hz), 2.68 (1H, t, J¼12.9 Hz), 2.26e2.13 (2H, m), 2.10 (1H, dd,
J¼12.9, 3.8 Hz), 2.05e1.88 (3H, m), 1.88e1.78 (1H, m), 1.68e1.59
(2H, m), 1.54e1.47 (2H, m),1.44 (3H, s),1.39 (3H, s), 0.98 (3H, s), 0.91
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.09.062.
(3H, d, J¼6.8 Hz). 13C NMR (100 MHz, CDCl3):
d 211.9 (C), 173.9 (C),
170.1 (CH), 115.4 (CH), 73.2 (CH2), 62.7 (C), 58.1 (CH), 52.4 (C), 43.4
(CH2), 41.6 (CH), 39.4 (CH), 38.8 (C), 35.9 (CH2), 23.2 (CH2), 22.3
(CH2), 20.1 (CH3), 17.9 (CH3), 17.2 (CH3), 16.8 (CH2), 16.2 (CH3). IR
(film, cmꢀ1): 2960, 1778, 1744, 1708, 1637, 1449, 1380, 1285, 1171,
1131, 1026, 887, 859. HRMS (EI) calcd for C20H29O4 (MþH)þ
333.2066, found 333.2081.
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Please cite this article in press as: Moussa, V. N.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.062

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Please cite this article in press as: Moussa, V. N.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.062