Synthetic approaches to phomactins: Novel oxidation of homoallylic alcohols using tetra-n-propylammonium perruthenate

Article abstract of DOI:10.1016/j.tet.2018.05.068

Previous studies of a synthesis of phomactin A had resulted in the synthesis of a 15-methylenebicyclo[9.3.1]pentadecadiene. The next step in the synthesis was to be the epoxidation of this methylenecyclohexane that was hoped would lead to a 1-(hydroxymethyl)cyclohexene by rearrangement of the exocyclic epoxide, but the epoxidation was difficult to carry out regioselectively on advanced intermediates. However, oxidation of a 15-methylenebicyclo[9.3.1]pentadeca-3,7-dien-14-ol using tetra-n-propylammonium perruthenate and N-methylmorpholine-N-oxide led to conversion of this homoallylic alcohol into the corresponding 14-oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carboxaldehyde in one step. Reduction of this using DIBAL-H gave a promising intermediate for a synthesis of a phomactin. The scope of this oxidation of homoallylic alcohols was briefly investigated.

Full text of DOI:10.1016/j.tet.2018.05.068

Accepted Manuscript
Synthetic approaches to phomactins: Novel oxidation of homoallylic alcohols using
tetra-n-propylammonium perruthenate
Timothy J. Blackburn, Eric J. Thomas
PII:
S0040-4020(18)30627-6
10.1016/j.tet.2018.05.068
TET 29575
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 March 2018
Revised Date: 22 May 2018
Accepted Date: 23 May 2018
Please cite this article as: Blackburn TJ, Thomas EJ, Synthetic approaches to phomactins: Novel
oxidation of homoallylic alcohols using tetra-n-propylammonium perruthenate, Tetrahedron (2018), doi:
10.1016/j.tet.2018.05.068.
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Synthetic approaches to phomactins: novel
oxidation of homoallylic alcohols using tetra-
n-propylammonium perruthenate
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Timothy J. Blackburn and Eric J. Thomas
The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthetic approaches to phomactins: novel oxidation of homoallylic alcohols using
tetra-n-propylammonium perruthenate
Timothy J. Blackburna and Eric J. Thomasa,
aThe School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK
ARTICLE INFO
ABSTRACT
Previous studies of
a synthesis of phomactin A had resulted in the synthesis of a 15-
Article history:
Received
Received in revised form
Accepted
methylenebicyclo[9.3.1]pentadecadiene. The next step in the synthesis was to be the epoxidation of
this methylenecyclohexane that was hoped would lead to a 1-(hydroxymethyl)cyclohexene by
rearrangement of the exocyclic epoxide, but the epoxidation was difficult to carry out regioselectively
on advanced intermediates. However, oxidation of a 15-methylenebicyclo[9.3.1]pentadeca-3,7-dien-
14-ol using tetra-n-propylammonium perruthenate and N-methylmorpholine-N-oxide led to conversion
of this homoallylic alcohol into the corresponding 14-oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-
carboxaldehyde in one step. Reduction of this using DIBAL-H gave a promising intermediate for a
synthesis of a phomactin. The scope of this oxidation of homoallylic alcohols was briefly investigated.
Available online
Keywords:
Keyword_1 natural products
Keyword_2 total synthesis
2009 Elsevier Ltd. All rights reserved
.
Keyword_3 oxidation
Keyword_4 tetra-n-propylammonium perruthenate
Keyword_5 regioselective epoxidation
1. Introduction
In our approach to phomactins, the cyclohexenylmethanol 5
was converted stereoselectively into the methylenecyclohexanol
6 using the Still variant of the 2,3-Wittig rearrangement.
Development of the side chain using a ytterbium(III) triflate
promoted vinyllithium addition to the corresponding aldehyde
gave the alcohol 7. Protection of this alcohol as its
benzyloxymethyl ether, conversion of the tert-butyldimethylsilyl
ether into the corresponding allylic bromide, and base mediated
cyclisation, gave the macrocyclic sulphone 8.5,6 This has the
bicyclo[9.3.1]pentadecadienyl structure found in the phomactins
and would appear to be a useful advanced intermediate for their
synthesis, see Figure 2.
The phomactins are a novel group of diterpenes originally
isolated from the marine fungus Phoma sp. although other
sources have since been identified. They are characterised by a
bicyclo[9.3.1]pentadecenyl skeleton as exemplified by
phomactins A, D, G and B2, 1 – 4, see Figure 1, and show
interesting biological activity including platelet activating factor
antagonism.1,2 They are recognised as challenging targets for
synthesis with many synthetic approaches and six total syntheses
reported to date.3,4 Phomactin A 1, in particular, has been the
focus of many synthetic studies with three total syntheses now
complete.
Figure 1 Structures of representative phomactins showing the
numbering scheme used.
———
Figure 2 Synthesis of the bicyclo[9.3.1]pentadecenyl sulfone 8.
Corresponding author. Tel.: +44 161 275 4613; e-mail: e.j.thomas@manchester.ac.uk

2
Tetrahedron
ACCEPTED MANUSCRIPT
A possible synthetic route from the sulfone 8 to phomactin A
1 is outlined in Figure 3. Reductive deprotection of the BOM-
protected hydroxysulfone 8 with concomittant loss of the
sulfonyl moiety would give the alcohol 9. Regioselective
epoxidation directed by the alcohol at C2 should then deliver the
bis-epoxide 10 possibly as a mixture of isomers.2a Oxidation of
the alcohol would lead to the ketone 11 but this should be
unstable with respect to isomerisation of the βγ-epoxide to the
corresponding allylic alcohol that would be expected to
equilibrate with the hemi-acetal 12 by analogy with the behaviour
of phomactins A 1 and G 3. Removal of the remaining silyl
protecting group, inversion of configuration at C14, and
intramolecular opening of the epoxide by the C14 alcohol,2b
would then provide phomactin A 1. We now describe studies of
the early stages of this scheme together with an unexpected
oxidation of homoallylic alcohols using tetra-n-propylammonium
perruthenate.7
Scheme 1 Epoxidation of the hydroxytriene 14 Reagents and
conditions i, TBAF, THF, rt, 16 h (95%); ii, Na, EtOH, NH3,
THF, 45 min (75%); iii, TBHP, VO(acac)2 (cat.), benzene, rt, 30
min (85%).
product 6 using either tert-butyl hydroperoxide and VO(acac)2 or
m-chloroperoxybenzoic acid gave the hydroxyepoxide 17 as
mixtures of diastereoisomers, ratio ca. 60 : 40 in both cases,
albeit the major isomer from the tert-butyl hydroperoxide
oxidation was the minor isomer from the per-acid epoxidation.
These hydroxyepoxides were not easy to separate but after
oxidation, the diastereoisomeric epoxyaldehydes 18 and 19 could
be separated, Scheme 2. The tert-butyl hydroperoxide
epoxidation should be directed by the homoallylic alcohol9 and
would be expected to give epoxyaldehyde 18 as the major
product after oxidation. Approach of the peracid to the less
hindered face of the alkene would give isomer 19 after oxidation.
1
These assignments were consistent with H NMR data and were
confirmed by an X-ray crystal structure of the epoxyaldehyde 18,
see Figure 4. However, preliminary studies of the addition of the
vinyllithium reagent derived from the vinylic iodide 20 to the
separated epoxyaldehydes 18 and 19 gave mixtures of products.
These were not properly characterised but, interestingly, side
products that involved epoxide cleavage did not appear to
predominate. However, the low stereoselectivity of epoxidation
of the methylenecyclohexane 6 and the formation of mixtures of
products from reactions of the aldehydes 18 and 19 with the
vinyllithium reagent led to this study being discontinued in
favour of studies of epoxidation of hydroxytriene 7.
Figure 3 Proposed development of a synthetic approach to
phomactin A 1 from the macrocyclic sulfone 8.
2. Results and discussion
2.1
Epoxidation
of
a
2-hydroxy-15-methylene-
bicyclo[9.3.1]pentadeca-3,7-diene and precursors
To avoid competing reduction of the benzene rings in the tert-
butyldiphenylsilyl ether, the macrocycle 8 was first desilylated
using tetra-n-butylammonium fluoride to give the alcohol 13 that
was converted into the diol 14 using Birch conditions.
Epoxidation of this dihydroxytriene using a small excess of tert-
butyl hydroperoxide and VO(acac)2 gave a good yield of a
monoepoxide derived from the 3,4-alkene. This was identified as
the stereoisomer 15 by analogy with previous work8 and was
consistent with a directed epoxidation on the more accessible
face of the 3,4-double-bond as indicated by the X-ray crystal
structure of the macrocyclic sulfone 8.5 However, attempts to
prepare the bis-epoxide 16 using prolonged reaction times, an
excess of the oxidant, or by using Ti(iPrO)4 or Mo(CO)6 as the
catalyst,9 were unsuccessful. Lower yields of the monoepoxide
15 were formed in these reactions with none of the required bis-
epoxide 16 being obtained, Scheme 1. It would appear that the
exocyclic double-bond is too hindered in this system, perhaps by
the 11-methyl group, for epoxidation to take place.
Scheme 2 Epoxidation of methylenecyclohexane 6 Reagents and
conditions i, either (a) TBHP, VO(acac)2, benzene, rt, 9 h (95%,
ratio 60:40) or (b) mCPBA, DCM, rt, 3 h (85%, ratio 40:60); ii,
Epoxidation of the methylenecyclohexane moiety of earlier
intermediates in the synthesis was considered as a way round this
problem since for these compounds the exocyclic double-bond
should be more accessible. Indeed epoxidation of the 2,3-Wittig
i
17 from TBHP epoxidation, py.SO3, Pr2NEt, DMSO, DCM, 0
oC, 15 min (18, 40%; 19, 25%).

3
ACCEPTED MANUSCRIPT
Although these investigations into the epoxidation of 2-
hydroxybicyclopentadecatrienes could have been continued, it
was decided instead to look at a second aspect of the proposed
synthesis of phomactin A 1, namely the introduction of the C14
alcohol with the required configuration. Indeed alcohol 25 should
be available by inverting the configuration of its epimer 13.
Following reductive desulfonylation and BOM-deprotection,
epoxidation directed by the hydroxyl group at C2 would then
give the epoxide 26. This should be unstable with respect to
isomerisation to the tetrahydropyran 27,8
intermediate for a synthesis of phomactin A 1, see Figure 5.
a
promising
Figure 4 X-Ray crystal structure of epoxyaldehyde 18
The products obtained from epoxidation of the hydroxytriene
7 varied significantly depending on the reaction conditions.
Using tert-butyl hydroperoxide and VO(acac)2 at room
temperature, the monoepoxide 21 was obtained regioselectively
as a 10:1 mixture of diastereoisomers, the threo-configuration
being assigned to the major diastereoisomer 21 by analogy with
the literature.10 Initial studies using m-chloroperoxybenzoic acid
gave the bis-epoxide 22 as a mixture of diastereoisomers, as well
as the monoepoxide 21. However, the use of tert-butyl
hydroperoxide and VO(acac)2 under microwave conditions11
gave the bis-epoxide 23, predominantly as one diastereoisomer,
in which the methylenecyclohexane had been epoxidised as well
as the 2,3-double-bond of the side-chain, Scheme 3.
Figure 5 Proposed epoxidation of an inverted C14 alcohol
2.2 Oxidation of 14-alcohols using tetra-n-propylammonium
perruthenate
Oxidation of the dihydroxyepoxide 15 was investigated first.
In the event, Parikh-Doering conditions using the pyridine.SO3
complex in dimethyl sulfoxide12 did not give the expected
diketone. Instead the major product was the dienone 28 identified
from spectroscopic data. The geometry of the newly introduced
double-bond was not confirmed, see Scheme 5.
Scheme 3 Epoxidation of the hydroxytriene 7 Reagents and
conditions i, TBHP, VO(acac)2, benzene, rt, 10 min (21, 78%);
ii, mCPBA, DCM, rt, 1.5 h (21, 15%, 22, 48%); iii, TBHP,
VO(acac)2, DCM, 60 oC microwave, 1 h (57%).
The formation of the bis-epoxide 23 from the microwave
promoted epoxidation of the hydroxytriene 7 using tert-butyl
hydroperoxide and VO(acac)2 was encouraging and so the
epoxidation of the macrocyclic dihydroxytriene 14 was examined
under these more forcing conditions. However the major product
was a 9:1 mixture of isomers of the bis-epoxide 24 in which the
7,8-double-bond had been epoxidised rather than the double-
bond of the methylenecyclohexane, see Scheme 4.
Scheme 5 Oxidation of dihydroxyepoxide 15 Reagents and
conditions i, iPr2NEt, py.SO3, DCM, DMSO, −7 oC, 5 min (50%).
Attempted oxidation of the conjugated diene 28 using singlet
oxygen (O2, Rose Bengal)13 gave a mixture of products and
reduction using several reagents was similarly inconclusive.
Oxidation of the hydroxytriene 13 was therefore investigated
since reduction of the resulting ketone away from the
macrocyclic ring was expected to give the required inverted
alcohol 25, see Scheme 6. Oxidation of the alcohol 13 using
pyridine.SO3-DMSO gave unchanged starting material, the Dess
Martin periodinane, pyridinium dichromate and pyridinium
chlorochromate gave complex mixtures of products, and a Swern
oxidation returned the starting material. However, oxidation
using
tetra-n-propylammonium
perruthenate
and
N-
methylmorpholine N-oxide14 gave a single product isolated in a
78% yield and identified as the keto-aldehyde 29, Scheme 6.
Scheme 4 Epoxidation of the dihydroxytriene 14 under forcing
conditions Reagents and conditions i, TBHP, VO(acac)2, DCM,
60 oC microwave, 30 min (15, 13%; 24, 31%).

4
Tetrahedron
initially formed non-conjugated ketone 38 into an enolate 39 that
ACCEPTED MANUSCRIPT
could be susceptible to further oxidation by ruthenium(VII)
possibly via an intermediate 40 with final fragmentation to the
ketoaldehyde 33,18 see Figure 7.
Scheme 6 Oxidation of the hydroxytriene 13 using TPAP
Reagents and conditions i, TPAP (cat.), NMO, 4Å sieves, DCM,
rt, 1 h (78%),
This oxidation of alcohol 13 has achieved several of the
transformations needed for a synthesis of phomactin A 1. Apart
from the intended oxidation of the alcohol at C14, the double-
bond migration and exocyclic carbon oxidation were the
conversions it had been hoped to carry out by the elusive
epoxidation of the methylenecyclohexane and isomerisation of
the resulting epoxide. The only similar TPAP oxidations in the
literature are the oxidations of derivatives of cholesterol 30 that
give the enediones 31.15 However, good yields were only
obtained for these reactions if they were promoted using
ultrasound, see Figure 6.
Figure 7 A rationalization of the TPAP-NMO oxidation of
homoallylic alcohols.
To progress a synthesis of phomactin A 1, the reduction of the
ketoaldehyde 29 was investigated. A Luche reduction converted
the aldehyde to the corresponding primary alcohol but only in a
low yield. However, reduction with di-isobutylaluminium
hydride was more efficient and gave the diol 41 that now has the
required configuration at C14, in an acceptable yield of 66%. The
configuration of the diol 41 at C14 was initially assigned on the
basis that the hydride would approach the ketone on its less
hindered face away from the phenylsulfonyl substituted
macrocyclic ring. This assignment was supported by a significant
nOe observed between the 12-methyl group and H-14 that
suggested that the 14-hydroxyl group was on the opposite side of
the six-membered ring from the 12-methyl group, Scheme 8.19
Deprotection of the BOM-protected dihydroxysulphone 41
followed by hydroxyl directed epoxidation would appear to be a
useful way forward for a synthesis of phomactin A. However in
his synthesis, Pattenden found that in some cases this epoxidation
was accompanied by competing epoxidation of the
tetrasubstituted 1,15-alkene.8 Although by judicious choice of
reaction conditions and substrate this side-reaction could be
minimised, in our case, the 3,4-epoxide 15 had already been
prepared and so its oxidation using TPAP-NMO was
investigated. A single major product was isolated from this
reaction but was identified as the ketolactone 42 not the expected
ketoaldehyde, see Scheme 8. It would appear that the initially
formed ketoaldehyde had suffered further oxidation, possibly of
the hemiacetal derived from the 2-hydroxyl group and exocyclic
aldehyde.14a,20 Preliminary attempts to reduce this lactone led to
mixtures of products that were not identified. To avoid formation
of this lactone, the 2-hydroxyl group of the dihydroxyepoxide 15
would have to be protected before the TPAP-NMO oxidation is
carried out. This work was more difficult than expected because
of stereochemical issues and will be reported in full elsewhere.7,21
Figure 6 Ultrasound promoted oxidation of cholesterol using
TPAP-NMO.
In our hands the efficient conversion of cholesterol 30 into the
enedione 31 did not need ultrasound but was relatively slow
(70% after 24 h). The oxidation of simpler homoallylic alcohols
using TPAP-NMO was also very briefly investigated, Scheme 7.
3-Methylenecyclohexanol 3216 gave 3-formylcyclohex-2-enone
33,17 54%, but only after 48 h. Oxidation of the open-chain
homoallylic alcohols 34a-c gave mixtures of the non-conjugated
ketones 35, together with the conjugated ketones 36 (for 24a,b)
and the ketoaldehydes 37, when the reactions were carried out
until no starting materials remained (8 – 94 h).
Scheme 7 TPAP-NMO oxidation of simple homoallylic alcohols
Reagents and conditions i, TPAP, NMO, 4 Å sieves, DCM, rt
(33, 48 h, 54%; 35a, 36a, 37a, 8 h, 74%, 10%, 16%; 35b, 36b,
37b, 24 h, 47%, 15%, 38%; 35c, 36c, 37c, 94 h, 63%, 0%, 26%).
3. Summary and conclusions
This paper reports work on the later stages of a proposed
synthesis of phomactin A 1. Studies of the epoxidation of 2-
hydroxy-15-methylenebicyclo[9.3.1]pentadeca-3,7-dienes
confirmed the regio- and stereo-selective introduction of the 3,4-
epoxide, but epoxidation of the exocyclic methylene group at
C15 was only possible on earlier intermediates and gave rise to
the formation of mixtures of stereoisomers during attempts to
The oxidation of homoallylic alcohols to unsaturated
ketoaldehydes using TPAP-NMO would seem to have some
generality albeit better yields were obtained in our hands for the
methylenecyclohexanols 13 and 32. The mechanism of this
reaction was not studied, but in the case of
a
3-
methylenecyclohexanol may involve the conversion of the

5
4.2.1
(1SR,2RS,10SR,11SR,12RS,14SR,3E,7E)-10-
ACCEPTED MANUSCRIPT
Benzenesulfonyl-2-benzyloxymethoxy-4,8,11,12-tetramethyl-15-
methylenebicyclo[9.3.1]pentadeca-3,7-dien-14-ol (13). Tetra-n-
butylammonium fluoride in THF (1 M, 16.6 mL, 16.6 mmol) was
added to the tert-butyldiphenylsilyl ether 8 (0.67 g, 0.83 mmol)
in THF (5.43 mL) at rt and the solution stirred at rt for 16 h.
Water (13 mL) was added and the aqueous phase extracted with
ethyl acetate (4 × 50 mL). The organic extracts were washed with
brine (100 mL), dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue (20:80 to 50:50
ether:light petroleum) gave the title compound 13 as a white
foam (0.45 g, 95%), Rf = 0.13 (50:50 ether:light petroleum);
νmax/cm-1 3513, 3063, 3030, 2932, 1662, 1620, 1448, 1383, 1301,
1268, 1143, 1024, 925, 736 and 697; δH (500 MHz, CDCl3) 7.71-
7.74 (2H, m, ArH), 7.19-7.46 (8H, m, ArH), 5.95 and 5.06 (each
1H, d, J 1.9, 15-CH), 4.98 (1H, dd, J 10.1, 2.2, 2-H), 4.81 (1H, d,
J 10.1, 3-H), 4.63 and 4.62 (each 1H, d, J 6.6, OHCHO), 4.57
and 4.47 (each 1H, d, J 11.7, PhHCH), 4.13 (1H, m, 7-H), 3.54
(1H, m, 14-H), 3.25 (1H, m, 10-H), 3.11 (1H, dt, J 14.8, 8.8, 13-
H), 3.01 (1H, dq, J 14.8, 7.3, 12-H), 2.72 (1H, dd, J 12.5, 2.2, 1-
H), 2.30-2.38 (2H, m, 9-H2), 1.73-1.90 (3H, m, 5-H2, 6-H), 1.57
(1H, m, 6-H′), 1.54 (3H, s, 8-CH3), 1.34 (3H, s, 11-CH3), 1.25
(1H, m, 13-H′), 1.20 (1H, m, OH) 1.13 (3H, s, 4-CH3) and 0.99
(1H, d, J 7.3, 12-CH3); δC (125 MHz, CDCl3) 145.9, 140.6,
138.4, 137.6, 133.2, 129.8, 128.7, 128.6, 128.4, 128.1, 127.6,
124.7, 120.4, 119.3, 92.2, 72.3, 69.6, 65.4, 62.7, 52.2, 49.4, 39.6,
38.8, 34.6, 34.3, 22.8, 22.2, 22.0, 17.3 and 16.2; m/z (ES+) 587.5
(M+ + 23, 100%); HRMS (ES+): MNa+, found 587.2798.
C34H44O5SNa requires 587.2802.
Scheme 8 Further modification of advanced intermediates
Reagents and conditions i, DIBAL-H, DCM, −78 C, 1 h (66%);
ii, TPAP (cat.), NMO, 4Å sieves, DCM, rt, 1 h (48%).
o
progress the synthesis. However, the oxidation of a 14-hydroxy-
15-methylenebicyclo[9.3.1]pentadeca-3,7-diene using TPAP-
NMO
was
very
useful
and
gave
a
14-
oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carboxaldehyde,
a promising intermediate for the completion of the synthesis. The
scope of this novel TPAP-NMO oxidation of homoallylic
alcohols was briefly examined and found to be more useful for 3-
methylenecyclohexanols than for open chain substrates. Its use
may well depend on the propensity of the initally formed non-
conjugated unsaturated ketone to undergo isomerisation to its
enol tautomer although further work is required if the full
potential of this reaction is to be realised. Nevertheless, this one-
pot conversion of an unsaturated non-conjugated ketone into a
conjugated keto-aldehyde is a novel reaction that may have other
applications in synthesis. In the next phase of our work on the
synthesis of phomactins, the TPAP-NMO oxidation was applied
to other macrocyclic epoxides to avoid formation of lactones
analogous to the ketolactone 42.21
4.2.2
(1SR,2RS,11SR,12RS,14SR,3E,7E)-15-Methylene-
4,8,11,12-tetramethylbicyclo[9.3.1]pentadeca-3,7-diene-2,14-
diol (14). The BOM-protected sulfone 13 (0.38 g, 0.68 mmol) in
THF (8.09 mL) and anhydrous ethanol (55 ꢀL) were added to
liquid NH3 (12.4 mL) at −78 ºC. Finely chopped sodium rinsed in
light petroleum was added portionwise until the solution retained
a blue colour. The cooling bath was then removed and the
reaction allowed to reflux for 45 min. Solid NH4Cl as added until
the solution had lost the blue colour, the white residue was
allowed to warm to rt, and the ammonia was allowed to
evaporate. Tetrahydrofuran (5 mL) was added, the mixture was
filtered through a pad of cotton wool and the filtrate was
concentrated under reduced pressure. The solid residue was
dissolved in water (5 mL) and the solution washed with ethyl
acetate (5 × 2.5 mL) then added to the remaining residue from the
filtration and the combined solution concentrated under reduced
pressure. Chromatography of the residue (50:50 ether:light
petroleum ether) gave the title compound 14 as an off white solid
(0.16 g, 75%), Rf = 0.21 (100% ether), mp 147-149 ºC; νmax/cm-1
3368, 3082, 2961, 2920, 1660, 1624, 1447, 1381, 1074, 1020,
978, 903 and 733; δH (500 MHz, CDCl3) 5.14 (1H, s, 15-CH),
5.07 (1H, d, J 8.5, 3-H), 5.00 (1H, s, 15-CH′), 4.60 (1H, m, 7-H),
4.14 (1H, m, 2-H), 4.04 (1H, m, 14-H), 2.34 (1H, br. s, 2-OH),
2.24 (1H, d, J 10.1, 1-H), 2.09-2.18 (2H, m, 6-H2), 1.88-2.01
(3H, m, 5-H2, 14-OH), 1.71-1.88 (3H, m, 9-H2, 10-H), 1.58 (1H,
dd, J 12.3, 6.6, 13-H), 1.47 (3H, s, 4-CH3), 1.44 (3H, s, 8-CH3),
1.28 (1H, dq, J 13.2, 6.6, 12-H), 1.17 (1H, m, 13-H′), 0.80 (3H,
d, J 6.6, 12-CH3), 0.73 (3H, s, 11-CH3) 0.40 (1H, m, 10-H′); δC
(125 MHz, CDCl3) 149.4, 139.6, 136.7, 128.5, 125.2, 117.6,
71.4, 70.1, 64.3, 42.3, 39.2, 38.3, 37.0, 35.5, 33.3, 22.9, 16.6,
15.9(2) and 15.8; m/z (ES+) 327.3 (M+ + 23, 80%); HRMS (EI+):
M+, found 304.2398. C20H32O2 requires 304.2397.
4. Experimental
4.1 General experimental details
Flash column chromatography was performed using Merck
silica gel 60H. Light petroleum refers to the fraction boiling
between 40 and 60 °C and was redistilled before use.
Tetrahydrofuran was dried over sodium-benzophenone and
distilled under nitrogen prior to use. Dichloromethane was dried
over CaH2 and distilled before use. Ether refers to diethyl ether.
Reactions under non-aqueous conditions were carried out under
an atmosphere of nitrogen or argon.
Mass spectra used electron impact ionisation (EI+), chemical
ionisation using ammonia (CI+) or electrospray ionisation in the
positive or negative modes (ES+, ES-). Low and high resolution
mass spectra were recorded using Micromass Trio 200 and
Kratos Concept IS spectrometers, respectively. Infra-red spectra
were measured using a Genesis FTIR spectrometer on NaBr
plates, either neat or as evaporated films. Nuclear magnetic
resonance spectra were recorded using Bruker Ultrashield 500
(500 MHz) and Varian INOVA 400 (400 MHz) spectrometers.
Coupling constants (J) are given in Hertz (Hz) and chemical
shifts are relative to tetramethylsilane. Residual non-deuteriated
solvent was used as the internal standard.
4.2.3
(1SR,2SR,3RS,5RS,12SR,13RS,15SR,8E)-5,9,12,13-
Tetramethyl-16-methylene-4-oxatricyclo[10.3.1.03,5]hexadec-8-
ene-2,15-diol (15). tert-Butyl hydroperoxide (5.5 M in decane, 14
ꢀL, 0.079 mmol) was added to dihydroxytriene 14 (20 mg, 0.065
4.2 Experimental procedures

6
Tetrahedron
ACCEPTED MANUSCRIPT
mmol) and VO(acac)2 (1.7 mg, 0.0065 mmol) in benzene (0.6
(55 mg, 40%), mp 154-156 ºC, Rf = 0.49 (50:50 ether:light
mL) at rt and the solution stirred at rt for 30 min. Saturated
aqueous Na2SO3 (2-3 drops) was added and the mixture was
stirred for 10 min, diluted with EtOAc (5 mL) and washed with
saturated aqueous NaHCO3 (5 mL). The aqueous phase was
extracted with EtOAc (4 × 10 mL) and the organic extracts were
washed with brine (10 mL), dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue (70:30
ether:light petroleum) gave the title compound 15 as a white solid
(18 mg, 85%), Rf = 0.43 (ether); νmax/cm-1 3430, 3082, 2960,
2924, 1622, 1450, 1384, 1244, 1204, 1077, 1037, 1015, 910, 872,
799, 731 and 678; δH (500 MHz, CDCl3) 5.22 and 5.13 (each 1H,
s, 16-CH), 4.78 (1H, dd, J 10.4, 1.3, 8-H), 4.14 (1H, m, 15-H),
3.47 (1H, br. d, J 11.0, 2-H), 2.99 (1H, s, 3-H), 2.60 (1H, s, 2-
OH), 2.41 (1H, d, J 11.0, 1-H), 2.12 (1H, m, 7-H), 2.03 (1H, m,
6-H), 1.91-2.08 (2H, m, 7-H′, 15-OH), 1.83-1.91 (3H, m, 10-H2,
11-H), 1.58 (1H, m, 14-H), 1.49 (3H, s, 9-CH3), 1.32 (1H, m, 13-
H), 1.18-1.27 (2H, m, 14-H′, 6-H′), 1.12 (3H, s, 5-CH3), 0.87
(3H, d, J 6.9, 13-CH3), 0.81 (1H, s, 12-CH3) and 0.67 (1H, m, 11-
H′); δC (125 MHz, CDCl3) 148.4, 137.1, 124.0, 119.4, 71.1, 65.6,
63.8, 62.3, 42.6, 38.2, 37.8, 36.9, 36.5, 32.9, 29.7, 23.8, 19.2,
17.0, 16.0 and 15.7; m/z (ES+) 343.3 (M+ + 23, 60%); HRMS
(EI+): M+, found 320.2346. C20H32O3 requires 320.2346.
petroleum); νmax/cm-1 3069, 2933, 2859, 1729, 1468, 1449, 1313,
1150, 1109, 1041, 912, 825 and 739; δH (500 MHz, CDCl3) 9.22
(1H, d, J 4.4, CHO), 7.84-7.89 (2H, m, ArH), 7.63-7.72 (5H, m,
ArH), 7.54-7.59 (2H, m, Ar-H), 7.39-7.49 (6H, m, ArH), 4.37
(1H, td, J 10.7, 4.8, 6-H), 3.24 (1H, d, J 2.4, 2-CH), 2.95 (1H, d,
J 15.9, 3-CH), 2.89 (1H, dd, J 10.7, 4.4, 1-H), 2.67 (1H, d, J
15.9, 3-CH′), 2.60 (1H, d, J 2.4, 2-CH′), 1.69 and 1.54 (each 1H,
m, 5-H), 1.48 (3H, s, 3-CH3), 1.44 (1H, m, 4-H), 1.03 [9H, s,
SiC(CH3)3] and 0.98 (3H, d, J 6.1, 4-CH3); δC (125 MHz, CDCl3)
203.4, 141.7, 136.2, 136.1, 134.2, 133.9, 133.1, 130.4, 130.1,
129.6, 128.1, 127.9, 127.7, 69.8, 61.8, 56.6, 56.0, 47.6, 42.4,
37.6, 37.0, 27.1, 19.4, 16.6 and 13.7. The second fraction was the
title compound 19 as a white solid, (35 mg, 25%), Rf = 0.41
(50:50 ether:light petroleum); νmax/cm-1 3069, 2930, 2857, 1729,
1466, 1451, 1314, 1151, 1109, 1039, 911, 825 and 737; δH (500
MHz, CDCl3) 9.51 (1H, d, J 3.0, CHO), 7.83-7.87 (2H, m, ArH),
7.68-7.74 (4H, m, ArH), 7.65 (1H, m, ArH), 7.55-7.60 (2H, m,
ArH), 7.41-7.52 (6H, m, ArH), 4.38 (1H, td, J 8.9, 4.6, 6-H), 3.27
(1H, dd, J 2.4, 1.0, 2-CH), 2.96 (1H, d, J 13.5, 3-CH), 2.89 (1H,
m, 1-H), 2.89 (1H, d, J 13.5, 3-CH′), 2.75 (1H, d, J 2.4, 2-CH′),
2.07 (1H, m, 4-H), 1.76 (1H, dt, J 13.5, 4.5, 5-H), 1.59 (1H, m, 5-
H′), 1.23 (3H, s, 3-CH3), 1.09 (3H, d, J 6.5, 4-CH3) and 1.06 [9H,
s, SiC(CH3)3]; δC (125 MHz, CDCl3) 200.8, 142.0, 136.2, 136.1,
134.2, 133.9, 133.4, 130.3, 130.1, 129.7, 128.1, 127.9, 127.6,
69.0, 60.7, 59.1, 59.2, 49.0, 44.0, 37.8, 34.6, 27.1, 19.4, 17.7 and
17.5; m/z (ES+) 599 (M+ + 23, 80%) and 179 (100); HRMS
(ES+): MNa+, found 599.2256. C33H40O5SSiNa requires 599.2258.
4.2.4
(1RS,3SR,4RS,6SR)-3-Benzenesulfonylmethyl-6-tert-
butyldiphenylsilyloxy-1-hydroxymethyl-3,4-dimethyl-2-
oxiranylcyclohexane (17). meta-Chloroperoxybenzoic acid (77%
in mineral oil, 40 mg, 0.18 mmol) was added to the
methylenecyclohexane 6 (50 mg, 0.088 mmol) in DCM (1.03
mL) at rt and the solution stirred at rt for 3 h. Dichloromethane
(10 mL) was added and the solution washed with aqueous NaOH
(0.1 M, 2 × 4 mL), water (8 mL) and brine (8 mL). The organic
phase was dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue (60:40 ether:light
petroleum) gave the title compound 17 as a glassy solid (45 mg,
85%), a 60:40 mixture of diastereoisomers (1H NMR), Rf = 0.4
(70% ether in light petroleum); νmax/cm-1 3520, 3071, 2957, 2932,
2858, 1588, 1444, 1428, 1308, 1150, 1111, 911, 829, 735 and
704; δH (500 MHz, CDCl3) 7.74-7.77 (2H, m, ArH), 7.60-7.66
(4H, m, ArH), 7.54 (1H, m, ArH), 7.43-7.47 (2H, m, ArH), 7.27-
7.41 (6H, m, ArH), 3.84-3.90 (1.6H, m, 6-H, 1-CH), 3.71 (0.4H,
m, 1-CH′), 3.70 (0.6H, dd, J 11.7, 2.4, 1-CH′), 3.64 (0.4H, m, 6-
H), 3.36 (0.4H, m, OH), 3.21 (0.6H, d, J 2.4, 2-CH), 3.16 (0.4H,
s, 2-CH), 3.15 (0.6H, d, J 2.4, 2-CH′), 2.88 (0.4H, d, J 2.0, 2-
CH′), 2.84 (0.4H, d, J 15.3, 3-CH), 2.83 (0.6H, d, J 15.3, 3-CH),
2.78 (0.4H, d, J 15.3, 3-CH′), 2.55 (0.6H, d, J 15.3, 3-CH′), 2.34
(0.4H, m, 1-H), 2.17 (0.6H, m, 1-H), 1.90 (0.4H, m, 4-H), 1.61
(0.6H, br s, OH), 1.53 (0.4H, dt, J 13.3, 4.3, 5-H), 1.34-1.42 (4H,
m, 5-H, 5-H′, 3-CH3), 1.14-1.22 (1.2H, m 5-H′, 4-H), 0.97 [9H, s,
SiC(CH3)3], 0.8 (1.2H, d, J 6.3, 4-CH3) and 0.67 (1.8H, d, J 6.7,
4-CH3); m/z (ES+) 596.4 (M+ + 18, 100%); HRMS (ES+):
4.2.6
(1RS,3SR,4RS,6SR)-1-[(1SR,2RS,3RS,6E)-8-tert-
Butyldimethylsilyloxy-3,7-dimethyl-2,3-epoxy-1-hydroxyoct-6-en-
1-yl]-3-benzenesulfonylmethyl-6-tert-butyldiphenylsilyloxy-3,4-
dimethyl-2-methylenecyclohexane (21). tert-Butyl hydroperoxide
(5.5 M in decane, 20 ꢀL, 0.108 mmol) was added to the
hydroxytriene 7 (20 mg, 0.024 mmol) and VO(acac)2 (1 mg,
0.004 mmol) in benzene (0.18 mL) at rt and the solution was
stirred at rt for 10 min. Saturated aqueous Na2SO3 (2-3 drops)
was added and the mixture was stirred for 10 min then diluted
with EtOAc (5 mL) and washed with saturated aqueous NaHCO3
(5 mL). The aqueous phase was extracted with EtOAc (4 × 10
mL) and the organic extracts were washed with brine (10 mL),
dried (Na2SO4), and concentrated under reduced pressure.
Chromatography of the residue (70:30 ether:light petroleum)
gave the title compound 21 as a white foam (16 mg, 78%)
containing 10% of a minor isomer (1H NMR), Rf = 0.50 (50:50
ether:light petroleum); νmax/cm-1 3479, 3071, 2957, 2931, 1631,
1589, 1462, 1448, 1428, 1309, 1255, 1149, 1108, 1083, 910, 837,
776, 741 and 704; δH (500 MHz, CDCl3) 7.76-7.79 (2H, m, ArH),
7.61-7.65 (4H, m, ArH), 7.52 (1H, m, ArH), 7.43-7.46 (2H, m,
ArH), 7.28-7.37 (6H, m, ArH), 5.25 (1H, m, 6′-H), 5.19 and 5.04
(each 1H, s, 2-CH), 4.09 (1H, m, 6-H), 3.94 (2H, s, 8′-H2), 3.70
(1H, m, 1′-H), 3.42 and 3.34 (each 1H, d, J 14.5, 3-CH), 2.66
(1H, d, J 6.3, 2′-H), 2.52 (1H, m, 1-H), 2.26 (1H, d, J 3.8, OH),
1.95 (2H, m, 5′-H2), 1.75 (1H, m, 4-H), 1.67 (1H, dt, J 14.2, 4.41,
5-H), 1.51 (3H, s, 7′-CH3), 1.45 (1H, m, 5-H′), 1.32 (3H, s, 3′-
CH3), 1.31-1.34 (2H, m, 4′-CH2), 1.16 (3H, s, 3-CH3), 0.95 and
0.84 [each 9H, s, SiC(CH3)3], 0.79 (3H, d, J 6.9, 4-CH3) and 0.00
(6H, s, 2 × SiCH3); δC (125 MHz, CDCl3) 149.6, 142.5, 135.9(2),
134.9, 134.1, 133.7, 133.3, 129.8, 129.2, 127.7, 127.6, 127.3,
123.4, 71.4, 70.2, 68.5, 65.0, 62.4, 43.9, 38.1, 36.3, 27.0, 26.0,
23.1, 21.3, 19.2, 18.4, 17.1, 16.7, 13.5 and −5.2; m/z (ES-) 867.5
([M + 35]-, 65%) and 865.5 ([M + 35]-, 100): HRMS (ES+):
MNa+, found 853.4335. C48H70O6SSi2Na requires 853.4324.
+
MNH4 , found 596.2853. C33H46O5NSSi requires 596.2860.
4.2.5 (1RS,2RS,3SR,4RS,6SR)- and (1RS,2SR,3SR,4RS,6SR)-
3-Benzenesulfonylmethyl-6-tert-butyldiphenylsilyloxy-3,4-
dimethyl-2-oxiranylcyclohexanecarbaldehydes (18) and (19). Di-
isopropylethylamine (0.205 mL, 1.17 mmol) was added to a
mixture of isomers of the hydroxyepoxide 17 (140 mg, 0.27
mmol) in DCM (1 mL) at rt and the solution cooled to 0 ºC
before the addition of the pyridine.SO3 (0.127 mg, 0.803 mmol)
in DMSO (1.1 mL). The solution was stirred at 0 ºC for 15 min
and then poured into brine (3.5 mL). The aqueous phase was
extracted into ethyl acetate (3 × 15 mL) and the organic extracts
were washed with saturated aqueous CuSO4 (50 mL), water (50
mL) and brine (50 mL), then dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue (50:50
ether:light petroleum) gave the title compound 18 as a white solid
4.2.7
(1RS,3SR,4RS,6SR)-1-[(1SR,2RS,3RS)-8-tert-
Butyldimethylsilyloxy-3,7-dimethyl-2,3,6,7-bisepoxy-1-
hydroxyoct-1-yl]-3-benzenesulfonylmethyl-6-tert-

7
butyldiphenylsilyloxy-3,4-dimethyl-2-methylenecyclohexane (22).
meta-Chloroperoxybenzoic acid (77% in mineral oil, 7 mg, 0.029
mmol) was aded to the hydroxytriene 7 (20 mg, 0.025 mmol) in
DCM (0.36 mL) at rt and the solution was stirred at rt for 1.5 h.
More meta-chloroperoxybenzoic acid (77% in mineral oil, 3 mg,
0.013 mmol) was added and the solution stirred at rt for 1 h.
Dichloromethane (5 mL) was added and the solution washed
with aqueous NaOH (0.1 M, 2 × 4 mL), water (4 mL) and brine
(4 mL). The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue (30:70
ether:light petroleum) gave the monoepoxide 21 (3.5 mg, 15%)
followed by the title compound 22 as a white foam (9 mg, 48%),
a 55:45 mixture of diastereoisomers with other very minor
isomers (1H NMR), Rf = 0.24 (70:30 ether: light petroleum);
epoxide 23, the dihydroxytriene 14 (20 mg, 0.064 mmol),
ACCEPTED MANUSCRIPT
VO(acac)2 (2.6 mg, 0.010 mmol) in DCM (0.53 mL) and tert-
butyl hydroperoxide (5.5 M in decane, 0.12 mL, 0.66 mmol),
after heating in a microwave reactor at 60 oC for 0.5 h and
chromatography (70:30 to 80:20 ether:light petroleum), gave
firstly the monoepoxide 15 as a thin clear film (3 mg, 13%)
containing ca. 25% of a minor diastereoisomer, Rf = 0.42 (ether);
HRMS (EI+): M+, found 320.2346. C20H32O3 requires 320.2346.
The second fraction was the title compound 24 as a white foam (7
mg, 31%), a 9:1 mixture of diastereoisomers (1H NMR), Rf =
0.24 (ether); νmax/cm-1 3436, 3082, 2960, 2929, 2360, 1722, 1625,
1453, 1422, 1387, 1304, 1249, 1075, 1027, 917, 796 and 732; δH
(500 MHz, CDCl3) major diastereoisomer 5.12 and 5.00 (each
1H, s, 17-CH), 4.30 (1H, dd, J 10.7, 7.2, 16-H), 3.56 (1H, dd, J
11.7, 4.4, 2-H), 2.96 (1H, d, J 4.4, 3-H), 2.65 (1H, s, 2-OH), 2.39
(1H, m, 1-H), 2.38 (1H, d, J 9.4, 8-H), 2.19 (1H, dt, J 13.6, 3.5,
15-H) 1.80-1.90 (3H, m, 11-H, 7-H2), 1.63-1.68 (3H, m, 11-H′,
6-H2), 1.52 (1H, s, 16-OH), 1.39 (1H, m, 14-H), 1.26 (1H, m, 15-
H′), 1.19 (3H, s, 10-CH3), 1.15 (3H, s, 5-CH3), 0.97 (1H, dd, J
13.0, 9.8, 12-H), 0.84 (3H, d, J 6.9 14-CH3), 0.74 (3H, s, 13-
CH3), 0.57 (1H, dd, J 13.0, 9.8, 12-H′); minor diastereoisomer
5.22 and 5.03 (each 1H, s, 17-CH), 4.20 (1H, m, 16-H) and 3.66
(1H, m, 2-H); m/z (ES+) 359.4 (M+ + 23, 100%); HRMS (ES+):
MNa+, found 359.2201. C20H32O4Na requires 359.2193.
ν
max/cm-1 3477, 3071, 2957, 2930, 2857, 1726, 1631, 1588, 1470,
1448, 1428, 1387, 1308, 1256, 1106, 1085, 909, 838, 778, 742
and 704; δH (500 MHz, CDCl3) 7.77-7.80 (2H, m, ArH), 7.62-
7.66 (4H, m, ArH), 7.54 (1H, m, ArH), 7.44-7.47 (2H, m, ArH),
7.30-7.38 (6H, m, ArH), 5.20 and 5.02 (each 1H, s, 2-CH), 4.10
(1H, m, 6-H), 3.74 (1H, m, 1′-H), 3.51-3.52 (2H, m, 8′-H2), 3.41
and 3.35 (each 1H, d, J 14.5, 3-CH), 2.70-2.76 (2H, m, 2′-H,
OH), 2.54 (1H, m, 1-H), 2.40 (0.55H, m, 6′-H), 2.34 (0.45H, m,
6′-H), 1.73 (1H, m, 4-H), 1.67 (1H, dt, 14.2, 4.7, 5-H), 1.35-1.51
(5H, m, 5-H′, 4′-H2, 5′-H2), 1.32 (3H, s, 3-CH3), 1.18-1.20 (6H,
m, 3′-CH3, 7′-CH3), 0.96 and 0.83 [each 9H, s, SiC(CH3)3], 0.78
(3H, d, J 6.6, 4-CH3) and −0.01 and −0.02 (each 3H, s, SiCH3);
m/z (ES+) 869.8 (M+ + 23, 100%); HRMS (ES+): MNa+ found
869.4271. C48H70O7SSi2Na requires 869.4273.
4.2.10
(3RS,5RS,12SR,13RS,8E)-5,9,12,13-Tetramethyl-16-
methylene-4-oxatricyclo[10.3.1.03,5]hexadeca-1,8-dien-15-one
(28). Di-isopropylethylamine (35 µL, 0.21 mmol) was added to
the dihydroxyepoxide 15 (15 mg, 0.046 mmol) in DCM (0.17
mL) at rt, the solution was cooled to to −7 ºC, and the
pyridine.SO3 complex (30 mg, 0.19 mmol) was added in DMSO
(0.19 mL). The reaction mixture was stirred at −7 º for 5 min then
poured into brine (3 mL). The aqueous phase was extracted with
EtOAc (4 × 6 mL) and the organic extracts washed with saturated
aqueous CuSO4 (10 mL), water (10 mL) and brine (10 mL), then
dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue (80:20 ether:light petroleum to
ether) gave the title compound 28 as a clear colourless oil (7 mg,
50%); νmax/cm-1 2918, 2851, 1694, 1618, 1453, 1384, 1230, 1183,
1062, 908 and 863; δH (500 MHz, CDCl3) 6.01 (1H, d, J 9.8, 2-
H), 5.36 and 5.03 (each 1H, s, 16-CH), 4.85 (1H, m, 8-H), 3.61
(1H, d, J 9.8, 3-H), 2.72 (1H, dd, J 16.7, 5.7, 14-H), 2.22 (1H,
dd, J 16.7, 3.2, 14-H′), 2.09-2.17 (2H, m, 7-H, 10-H), 2.05 (1H,
dt, J 12.9, 3.5, 11-H), 1.98 (1H, m, 10-H′), 1.91 (1H, dt, J 10.1,
4.1, 7-H′) 1.78 (1H, dqd, J 13.6, 6.9, 3.2, 13-H), 1.71 (1H, dt, J
13.9, 4.1, 6-H), 1.50 (1H, m, 6-H′), 1.48 (3H, s, 9-CH3), 1.14
(3H, s, 5-CH3), 1.05 (1H, m, 11-H′), 1.05 (3H, s, 12-CH3) and
0.84 (3H, d, J 6.9, 13-CH3); δC (125 MHz, CDCl3), 199.1, 144.2,
143.8, 134.9, 133.4, 123.8, 114.3, 62.7, 59.2, 43.2, 38.1, 37.8,
34.1, 33.2, 28.7, 23.4, 19.2, 16.0, 15.2 and 14.3; m/z (ES+) 301
(M+ + 1, 100%); HRMS (EI+): M+, found 300.2085. C20H28O2
requires 300.2084.
4.2.8
(1RS,3SR,4RS,6SR)-1-[(1SR,2RS,3RS,6E)-8-tert-
Butyldimethylsilyloxy-3,7-dimethyl-2,3-epoxy-1-hydroxyoct-6-en-
1-yl]-3-benzenesulfonylmethyl-6-tert-butyldiphenylsilyloxy-3,4-
dimethyl-2-oxiranylcyclohexane (23). tert-Butyl hydroperoxide
(5.5 M in decane, 44 ꢀL, 0.245 mmol) was added to the
hydroxytriene 7 (20 mg, 0.024 mmol) and VO(acac)2 (1 mg,
0.004 mmol) in DCM (0.2 mL) at rt and the solution heated at 60
ºC in a microwave reactor for 1 h. Saturated aqueous Na2SO3 (2-3
drops) was added, the mixture was stirred at rt for 10 min, and
EtOAc (5 mL) was added. The solution washed with saturated
aqueous NaHCO3 (5 mL) and the aqueous phase was extracted
with EtOAc (4 × 10 mL). The organic extracts were washed with
brine (10 mL), dried (Na2SO4), and concentrated under reduced
pressure. Chromatography of the residue (20:80 to 30:70
ether:light petroleum) gave the title compound 23 as yellow gum
(12 mg, 57%); Rf = 0.22 (50:50 ether:light petroleum); νmax/cm-1
3483, 3071, 2957, 2930, 2857, 1726, 1686, 1588, 1462, 1447,
1428, 1388, 1320, 1253, 1152, 1110, 1084, 837, 778, 741 and
704; δH (500 MHz, CDCl3) 7.77-7.67 (6H, m, ArH), 7.53 (1H, m,
ArH), 7.44-7.47 (2H, m, ArH), 7.41-7.31 (6H, m, ArH), 5.30
(1H, m, 6′-H), 4.12 (1H, dt, J 10.4, 4.4, 6-H), 3.95 (2H, s, 8′-H2),
3.38 (1H, m, 1′-H), 3.32 (1H, m, 2′-H), 3.04 (1H, m, 2-CH),
2.91-2.95 (2H, m, 2-CH′, 3-CH), 2.84 (1H, d, J 14.8, 3-CH′),
2.05-2.11 (3H, m, 1-H, 5′-H2), 1.74 (1H, m, 4-H), 1.53 (3H, s, 7′-
CH3), 1.39-1.60 (4H, m, 5-H2, 4′-H2), 1.24 (3H, s, 3′-CH3), 0.98
and 0.85 [each 9H, s, SiC(CH3)3], 0.84 (3H, s, 3-CH3), 0.76 (3H,
d, J 6.9, 4-CH3) and 0.00 (6H, s, 2 × SiCH3); δC (125 MHz,
CDCl3) 142.2, 135.8, 135.7, 135.1, 134.5, 133.4, 133.0, 130.0,
129.7, 129.3, 127.9, 127.6, 127.3, 123.3, 68.5, 67.4, 66.7, 61.7,
61.1, 60.4, 49.1, 43.9, 38.7, 29.7, 27.1, 26.6, 26.0, 25.8, 25.7,
23.5, 19.3, 18.4, 17.2, 16.7, 13.5 and −5.2; m/z (ES+) 906.2
(100%) and 869.7 (M+ + 23, 82); HRMS (ES+): MNa+ found
869.4294. C48H70O7SSi2Na requires 869.4273.
4.2.11 (2RS,10SR,11SR,12RS,3E,7E)-10-Benzenesulfonyl-2-
benzyloxymethoxy-4,8,11,12-tetramethyl-14-
oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carbaldehyde
(29). N-Methylmorpholine-N-oxide (10 mg, 0.088 mmol) was
added to a suspension of the alcohol 13 (10 mg, 0.017 mmol) and
4Å molecular sieves (8 mg) in DCM (0.41 mL) and the mixture
was stirred for 10 min at rt. Tetra-n-propylammonium
perruthenate (1 mg, 0.0026 mmol) in DCM (0.1 mL) was added
and the mixture stirred for 1 h. Dichloromethane (1 mL) was
added and the mixture was filtered through celite with copious
washings of ether. The filtrate was washed with aqueous Na2S2O3
(20 mL) and brine (20 mL), and the aqueous layer was extracted
with ether (1 × 30 mL). The organic extracts were dried (MgSO4)
and concentrated under reduced pressure. Chromatography of the
4.2.9
(1SR,2SR,3RS,5RS,13SR,14RS,16SR)-5,10,13,14-
Tetramethyl-17-methylene-4,9-bis-
oxatetracyclo[11.3.1.03,5.08,10]heptadecane-2,16-diol
(24).
Following the procedure outlined for the synthesis of the bis-

8
Tetrahedron
ACCEPTED MANUSCRIPT
residue (40:60 ether:light petroleum) gave the title compound
m, 7-H), 4.71 and 4.67 (each 1H, d, J 6.9, OHCHO), 4.67 (1H,
29 as a yellow viscous oil (8 mg, 78%), Rf = 0.39 (40:60
ether:light petroleum); νmax/cm-1 3066, 2923, 1675, 1449, 1303,
1146, 1026, 911 and 729; δH (500 MHz, CDCl3) 10.58 (1H, s, 15-
CHO), 7.8-7.82 (2H, m, ArH), 7.57 (1H, m, ArH), 7.47-7.50 (2H,
m, ArH), 7.19-7.29 (5H, m, ArH), 5.76 (1H, d, J 9.5, 2-H), 4.98
(1H, d, J 9.5, 3-H), 4.69 and 4.63 (each 1H, d, J 6.9, OHCHO),
4.57 (1H, m, 7-H), 4.48 and 4.43 (each 1H, d, J 11.7, PhHCH),
3.61 (1H, m, 12-H), 3.43 (1H, d, J 6.6, 10-H), 3.13 (1H, dd, J
16.7, 7.3, 9-H), 3.08 (1H, dd, J 19.9, 5.7, 13-H), 2.44 (1H, d, J
16.7, 9-H′), 2.41 (1H, dd, J 19.9, 5.7,13-H′), 1.98 (1H, m, 6-H),
1.85-1.94 (2H, m, 5-H2), 1.74 (1H, m, 6-H′), 1.53 (3H, s, 8-CH3),
1.39 (3H, s, 4-CH3), 0.98 (3H, d, J 7.0,12-CH3) and 0.47 (3H, s,
11-CH3); δC (125 MHz, CDCl3) 197.8, 197.2, 151.0, 146.9,
139.9, 138.2, 137.5, 133.9, 131.2, 129.6, 129.3, 129.0, 128.4,
128.0, 127.8, 126.2, 92.8, 69.7, 67.7, 65.0, 46.34, 42.2, 38.1,
35.8, 35.4, 25.6, 21.0, 16.5, 15.7 and 13.5; m/z (ES+) 594.5 (M+ +
m, 15-CH), 4.59 and 4.48 (each 1H, d, J 12.0, PhHCH), 4.09
(1H, m, 14-H), 3.93 (1H, t, J 12.0, OH) 3.63 (1H, d, J 6.6, 10-H),
3.45 (1H, dd, J 11.3, 1.6, 15-CH′), 3.19 (1H, m, 12-H), 2.44 (1H,
d, J 17.0, 9-H), 2.14 (1H, dd, J 17.0, 7.9, 9-H′), 2.09 (1H, m, 6-
H), 1.93-2.04 (4H, m, 5-H2, 13-H2), 1.82 (1H, m, 6-H′), 1.58 (3H,
s, 8-CH3), 1.49 (3H, s, 4-CH3), 1.20 (1H, m, 14-OH), 0.92 (1H, d,
J 6.9, 12-CH3) and 0.66 (3H, s, 11-CH3); δC (125 MHz, CDCl3),
142.5, 141.9, 140.3, 137.8, 137.6, 133.5, 131.7, 129.2, 128.8,
128.6, 127.9, 127.8, 125.3(2), 92.4, 72.9, 69.9, 68.1, 66.0, 60.4,
45.9, 39.1, 37.0, 36.6, 26.2, 19.2, 16.2, 15.9 and 13.8; m/z (ES+)
603.0 (M+ + 23, 100%); HRMS (ES+): MNa+, 603.2760.
C34H44O6SNa requires 603.2751.
4.2.14
(4SR,5RS,7RS,14SR,15RS,10E)-7,11,14,15-
Tetramethyl-3,6-bis-oxatetracyclo[12.4.04,18.05,7]octadeca-
1(18),10-diene-2,17-dione (42). Following the procedure outlined
for the synthesis of the keto-aldehyde 29, the epoxydiol 15 (10
mg, 0.031 mmol), 4Å molecular sieves (8 mg), TPAP (2 mg,
0.05 mmol) and NMO (18 mg, 0.16 mmol) in DCM (0.8 mL),
after chromatography (40:60 ether:light petroleum), gave the title
compound 42 as a white viscous oil (4 mg, 48%), Rf = 0.79
(50:50 ether:light petroleum); νmax/cm-1 2918, 2850, 1766, 1694,
1455, 1392, 1262, 1158, 1047, 912, 870, 792 and 731; δH (500
MHz, CDCl3) 4.94 (1H, d, J 6.6, 4-H), 4.85 (1H, m, 10-H), 2.69
(1H, ddd, J 15.8, 13.6, 2.5, 12-H), 2.61 (1H, ddq, J 18.9, 13.2,
6.9, 15-H), 2.50 (1H, d, J 6.6, 5-H), 2.33-2.40 (2H, m, 16-H2),
2.29 (1H, m, 12-H′), 1.90 (1H, m, 13-H), 1.89 (1H, ddd, J 15.8,
5.0, 2.5, 8-H), 1.77 and 1.67 (each 1H, m, 9-H), 1.54 (1H, dd, J
5.3, 2.2, 13-H′), 1.48 (4H, m, 8-H′, 11-CH3), 1.33 (1H, s, 7-CH3),
1.16 (1H, s, 14-CH3) and 0.97 (1H, d, J 6.9, 15-CH3); m/z (ES+)
353.2 (M+ + 23, 100%); HRMS (ES+): MH+, 331.1917. C20H27O4
requires 331.1904.
+
18, 100%); HRMS (ES+): MNH4 , 594.2887. C34H44O6NS
requires 594.2884.
4.2.12 Cyclohex-2-en-1-one-3-carbaldehyde (33).17 4Ǻ
Molecular sieves (450 mg), NMO (370 mg, 3.12 mmol) and
TPAP (50 mg, 0.14 mmol) were added to 3-
methylenecyclohexanol 3216 (100 mg, 0.89 mmol) in
dichloromethane (10 mL) and the resulting mixture was stirred at
rt for 84 h then filtered through a short pad of silica (DCM).
After concentration under reduced pressure, chromatography of
the residue (30:70 to 50:50 ether:light petroleum) gave the title
compound 3317 as a white solid (60 mg, 0.48 mmol, 54%), Rf =
0.42 (25:75 EtOAc:light petroleum); δH (400 MHz, CDCl3) 9.79
(1H, s, CHO), 6.56 (1H, t, J 1.7, 2-H), 2.53-2.57 (2H, m, 4-H2),
2.50 (2H, m, 6-H2) and 2.08 (2H, quintet, J 6.5, 5-H2); δC (125
MHz, CDCl3) 200.5, 194.5, 154.5, 139.5, 38.6, 21.8 and 21.5;
m/z (EI+) 124 (M+, 100%).
4.3. X-ray data.
The same procedure with reaction times as indicated in the
text gave mixtures of products as outlined in Scheme 7; 37a
(16%); δH (400 MHz, CDCl3) 9.81 (1H, d, J 7.1, 5-H), 6.85 (1H,
d, J 16.6, 3-H), 6.76 (1H, dd, J 16.6, 7.1, 4-H) and 2.4 (3H, s, 1-
H3); 37b (38%); δH (400 MHz, CDCl3) 9.78 (1H, d, J 7.3, 6-H),
6.99 (1H, d, J 16.1, 4-H), 6.82 (1H, dd, J 16.1, 7.3, 5-H), 2.95
(1H, sept, J 6.8, 2-H) and 1.12 (6H, d, J 6.8, 1-H3, 2-CH3); 37c
(28 mg, 0.17 mmol, 26%) as a white solid, Rf = 0.32 (30:70
ether:light petroleum); νmax/cm-1 2927, 2854, 1705, 1692, 1449,
1375, 1061, 977, 734, 701, 684, 653 and 617; δH (400 MHz,
CDCl3) 9.79 (1H, d, J 7.3, 4-H), 6.99 (1H, d, J 15.9, 2-H), 6.83
(1H, dd, J 15.9, 7.6, 3-H), 2.69 (1H, tt, J 10.9, 3.3, 1′-H) and 1.2-
1.9 (10H, m); m/z (EI+) 166 (M+, 100%).
X-ray data for epoxyaldehyde 18 were collected at a temperature
of 100 K using a using Mo-Kα radiation on an Oxford X’calibur
diffractometer, equipped with an Oxford Cryosystems Cobra
nitrogen flow gas system. Data were measured using CrysAlisPro
suite of programs. Absorption correction was performed using
empirical methods based upon symmetry-equivalent reflections
combined with measurements at different azimuthal angles. The
crystal structure was solved and refined against all F2 values
using the SHELXL and OLEX 2 suite of programs. Atoms were
refined anisotropically. Hydrogen atoms were placed in
calculated positions refined using idealized geometries (riding
model) and assigned fixed isotropic displacement parameters.
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
a/Å
b/Å
c/Å
α/°
β/°
C33H40O5SSi
576.80
100
monoclinic
P21/n
7.9940(9)
16.6550(18)
22.846(2)
90
93.232(2)
90
3036.9(6)
4
1.262
0.186
4.2.13
(2RS,10SR,11SR,12RS,14RS,3E,7E)-10-
Benzenesulfonyl-2-benzyloxymethoxy-15-hydroxymethyl-
4,8,11,12-tetramethylbicyclo[9.3.1]pentadeca-1(15),3,7-trien-14-
ol (41). Di-isobutylaluminium hydride (54 ꢀL, 0.054 mmol) was
added to the keto-aldehyde 29 (9 mg, 0.0156 mmol) in DCM (0.3
mL) at −78 ºC and the solution stirred at −78 oC for 1 h.
Methanol was added and the mixture stirred at at −78 ºC for 10
min then allowed to warm to rt. Aqueous Rochelle’s salt (5%, 0.5
mL) and EtOAc (0.5 mL) were added and the mixture was stirred
for 20 min then diluted with water (1 mL). The aqueous phase
was extracted with EtOAc (4 × 2 mL) and the organic extracts
were washed with brine (5 mL), dried (Na2SO4) and concentrated
under reduced pressure. Chromatography of the residue (30:70 to
80:20 ether:light petroleum) gave the title compound 41 as a
viscous oil (6 mg, 66%), Rf = 0.48 (80:20 ether:light petroleum);
νmax/cm-1 3500, 2916, 2848, 1446, 1386, 1295, 1146, 1083, 1023,
909 and 727; δH (500 MHz, CDCl3) 7.80-7.82 (2H, m, ArH), 7.55
(1H, m, ArH),7.45-7.49 (2H, m, ArH), 7.24-7.31 (5H, m, ArH),
5.53 (1H, dd, J 8.5, 0.6, 3-H), 5.10 (1H, d, J 8.5, 2-H), 4.73 (1H,
γ/°
Volume/Å3
Z
ρcalcg/cm3
ꢀ/mm-1
F(000)
1232.0
0.25 × 0.15 × 0.05
Crystal size/mm3

9
4. For total syntheses: (a) Miyaoka, H.; Saka, Y.; Miura, S.;
Radiation
MoKα (λ = 0.71073)
ACCEPTED MANUSCRIPT
Yamada, Y. Tetrahedron Lett. 1996, 37, 7107; (b) Goldring, W. P.
D.; Pattenden, G. Chem. Commun. 2002, 1736; (c) Diaper, C. M.;
Goldring, W. P. D.; Pattenden, G. Org. Biomol. Chem. 2003, 1,
3949; (d) Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003,
125, 1712. (e) Goldring, W. P. D.; Pattenden, G. Org. Biomol.
Chem. 2004, 2, 466; (f) Huang, J.; Wu, C.; Wulff, W. D. J. Am.
Chem. Soc. 2007, 129, 13366; (g) Tang, Y.; Cole, K. P.;
Buchanan, G. S.; Li, G,; Hsung, R. P. Org. Lett. 2009, 11, 1591;
(h) Buchanan, G. S.; Cole, K. P.; Tang, Y.; Hsung, R. P. J. Org.
Chem. 2011, 76, 7027.
2Θ range for data collection/° 3.572 to 50.698
Index ranges
-9 ≤ h ≤ 9, -18 ≤ k ≤ 20, -27 ≤ l ≤ 24
16142
5542 [Rint = 0.0830, Rsigma = 0.1672]
5542/27/385
0.710
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I>=2σ (I)] R1 = 0.0436, wR2 = 0.0550
Final R indexes [all data] R1 = 0.1070, wR2 = 0.0641
5. Blackburn, T. J.; Kilner, M. J.; Thomas, E. J. Tetrahedron 2015,
71, 7293.
6. For earlier studies see: (a) McGowan, G.; Thomas, E. J. Org. Biol.
Chem. 2009, 7, 2576; (b) Shapland, P. D. P.; Thomas, E. J.
Tetrahedron 2009, 65, 4201.
7. Part of this work was initially reported in this communication:
Blackburn, T. J.; Helliwell, M.; Kilner, M. J.; Lee, A. T. L.;
Thomas, E. J. Tetrahedron Lett. 2009, 50, 3550.
8. For a discussion of the stereoselectivity of epoxidation of 2-
hydroxybicyclo[9.3.1]pentadeca-3,7-dienes, see reference (2a).
9. For directed epoxidation of homoallylic alcohols see: Mihelich, E.
D.; Daniels. K.; Eickhoff, D. J. J. Am. Chem. Soc. 1981, 103,
7690.
CCDC 1830872 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html
(or
from
the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
5 Acknowledgments
10. Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
11. (a) Torres, G.; Torres, W.; Prieto, J. A. Tetrahedron 2004, 60,
10245; (b) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
12. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
13. (a) Cole, K. P.; Hsung, R. P. Chem. Commun. 2005, 5784; (b)
Wood, J. L.; Graeber, J. K.; Njardarson, J. T. Tetrahedron 2003,
59, 8855.
14. (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639; (b) Griffith, W. P.; Ley, S. V.; Whitcombe,
G. P.; White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625.
15. (a) Miranda Moreno, M. J. S.; Sá e Melo, M. L.; Campos Neves,
A. S. Tetrahedron Lett. 1991, 32, 3201; (b) Acosta, C. K.; Rao, P.
N.; Kim, H. K. Steroids, 1993, 58, 205.
We thank the EPSRC for a studentship (to T. J. B.) and
Eleanor Renwick for the studies of 3-methylenecyclohexanol 32
and the homoallylic alcohols 34.
6 References and notes
1. (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.;
Kuwano, H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113,
5463; (b) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Kuwano,
H.; Hata, T. J. Antibiot. 1995, 48, 1188.
2. For reviews of the chemistry of phomactins see: (a) Ciesielski, J.;
Frontier, A. J. Org. Prep. Proc. Int. 2014, 46, 214; (b) Goldring,
W. P. D.; Pattenden, G. Acc. Chem. Res. 2006, 39, 354.
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1307.
17. Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452.
18. Chandler, W. D.; Wang, Z.; Lee, D. G. Canad. J. Chem. 2005, 83,
1212.
19. The configuration of the diol 41 was subsequently confirmed by
an X-ray structure determination of a later intermediate; see ref 7.
20. Dias, L. C.; Ferreira, A. A.; Diaz, G. Synlett 2002, 11, 1845.
21. Burnell, E. S.; Irshad, A.-R.; Raftery, J.; Thomas, E. J.
Tetrahedron Lett. 2015, 56, 3255.
3. For representative approaches see: (a) Ryu, K.; Cho, Y.-S.; Jung,
S.-I.; Cho, C.-G. Org. Lett. 2006, 8, 3343; (b) Teng, D.; Wang,
B.; Augatis, A. J.; Totah, N. I. Tetrahedron Lett. 2007, 48, 4605;
(c) Huang, J.; Wang, H.; Wu, C.; Wulff, W. D. Org. Lett. 2007, 9,
2799; (d) Goldring, W. P. D.; Alexander, S. P. H.; Kendall, D. A.;
Pattenden, G. Bioorg. Med. Chem. Lett. 2005, 15, 3263; (e) You,
L.-F.; Hsung, R. P.; Bedermann, A. A.; Kurdyumov, A. V.; Tan,
Y.; Buchanan, G. S.; Cole, K. P. Adv. Synth. Cat. 2008, 350, 2885;
(f) Schwartz, K. D.; White, J. D. Org. Lett. 2011, 13, 248; (g)
Huang, S.; Du, G.; Lee, C.-S. J. Org. Chem. 2011, 76, 6534; (h)
Buchanan, G. S.; Cole, K. P.; Li, G.; Tang, Y.; You, L.-F.; Hsung,
R. P. Tetrahedron 2011, 67, 10105; (i) Ciesielski, J.; Cariou, K.;
Frontier, A. J. Org. Lett. 2012, 14, 4082; (j) Ciesielski, J.; Gandon,
V.; Frontier, A. J. J. Org. Chem. 2013, 78, 9541.
Supplementary information
1
Copies of H and 13C NMR spectra have been deposited as
supplementary data.