Synthesis of precursors of phomactins using [2,3]-Wittig rearrangements

Article abstract of DOI:10.1016/j.tet.2009.03.031

o-Toluic acid has been converted into methyl (8RS,9SR)-7-(bromomethyl)-8,9-dimethyl-1,4-dioxaspiro[4.5]dec-6-ene-8-carboxylate, the stereochemical defining step being a conjugate addition of lithium dimethylcuprate to a cyclohexadienone prepared using a B

Full text of DOI:10.1016/j.tet.2009.03.031

Tetrahedron 65 (2009) 4201–4211
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Synthesis of precursors of phomactins using [2,3]-Wittig rearrangements
*
Peter D.P. Shapland, Eric J. Thomas
The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 January 2009
Received in revised form 12 March 2009
Accepted 13 March 2009
Available online 21 March 2009
o-Toluic acid has been converted into methyl (8RS,9SR)-7-(bromomethyl)-8,9-dimethyl-1,4-dioxaspiro-
[4.5]dec-6-ene-8-carboxylate, the stereochemical defining step being a conjugate addition of lithium
dimethylcuprate to a cyclohexadienone prepared using a Birch reduction followed by an allylic oxidation.
Displacement of the bromide with various propargylic alcohols followed by reduction of the ester and
protection of the primary alcohol so formed then gave a series of propargyl cyclohexenylmethyl ethers.
[2,3]-Wittig rearrangements of these and related propargylic ethers were studied as an approach to
precursors of phomactins. The rearrangements were found to proceed by regioselective deprotonation of
the propargylic side-chain to give substituted methylenecyclohexanes but mixtures of stereoisomers
were obtained.
Aspects of the chemistry of the Wittig rearrangement products were investigated including epoxidation,
oxidation of the side-chain hydroxyl groups to give 2-ynones and reactions of the 2-ynones with lithium
dimethylcuprate. The propargyl side-chain of a Wittig rearrangement precursor was elaborated to pre-
pare an intermediate, which was fully functionalised for incorporation into a phomactin.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
substituted methylenecyclohexanes. Preliminary studies,10 see
Scheme 1, showed that 1-(3-methylbut-2-enyloxymethyl)cyclohex-
The phomactins are a group of diterpenes, which have in-
teresting biological activity and which have attracted considerable
interest from synthetic organic chemists.1 Phomactin D 1 was the
first member of the series to succumb to total synthesis,2 and since
then two syntheses of phomactin A 23,4 and syntheses of pho-
mactins B2 35 and G6 have been reported, along with many con-
tributions on alternative approaches to phomactins.7 The chemistry
of phomactins has been reviewed.8
1-ene 4 rearranged on treatment with n-butyllithium with
O
Me
Me
Me
OH
HO
n
Me
BuLi
26%
not
Me
Me
Me
4
5
6
Me
OH
OHC
O
O
O
O
H
OH
OH
15
Me
H
O
Me
Me
1
n
BuLi
75%
11
12
Li
Me
O
Me
Me
Me
H
Me
9
8
Me
7
Me
O
OH
2
O
O
1
H
Me
Me
n
Me
BuLi
75%
TBSO
O
O
TBSO
Me
Me
Me
H
O
Me
OH
O
10
11
3
Oxid.;
Me
O
O
Me
Me
MeLi, CuI;
PPTS, H2O
In planning a new approach to phomactins, [2,3]-Wittig rear-
rangements9 were considered for the synthesis of suitably
TBSO
Me
12
* Corresponding author.
Scheme 1. Preliminary studies of the synthesis of 2-(1-hydroxyalk-2-ynyl)-1-methyl-
E-mail address: e.j.thomas@manchester.ac.uk (E.J. Thomas).
enecyclohexanes by [2,3]-rearrangements.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.031

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P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
OH
Me
2
O
Me
1'
PhS(O)2
Me
Li
PhS(O)2
3
Me
OP
OP
Me
Me
Me
OP
13
14
O
H
Me
OP
Me
OP
Phomactins
Me
(P = protecting groups)
15
Scheme 2. An approach to precursors of phomactins using
a [2,3]-Wittig
rearrangement.
deprotonation of the more acidic ethereal methylene group next to
the six-membered ring to give 1-(2,2-dimethyl-1-hydroxybut-3-
en-1-yl)cyclohexene 5 and not 2-(1-hydroxy-3-methylbut-2-enyl)-
1-methylenecyclohexane 6.10 However, the corresponding alkyne 7
Figure 1. An ORTEP representation of the structure of the methyl ester 20 as de-
termined by X-ray crystallography.
with macrocycle formation by sulfone alkylation,2 could then give
access to bicyclic precursors of phomactins, e.g., the ketone 15. We
now report studies into Wittig rearrangements of several 1-(alk-2-
ynyloxymethyl)cyclohexenes and aspects of the chemistry of the
products so formed. Of interest in the context of a phomactin
synthesis is the stereoselectivity of these Wittig rearrangements
with respect to the newly formed stereogenic centres at C(2) and
C(10), and the subsequent conversion of the alkyne into a tri-
substituted alkene.
rearranged via the lithiated intermediate
9 to give the 2-
(1-hydroxybut-2-ynyl)-1-methylenecyclohexane 8, and rearrange-
ment of the slightly more complex propargyl allyl ether 10 gave the
methylenecyclohexane 11. In both cases mixtures of stereoisomers
were obtained. Alcohol 11 was taken through to the unsaturated
diketone 12 by oxidation, conjugate addition and hydrolysis of the
acetal with migration of the exocyclic double-bond.10
Based on these preliminary observations, a synthetic approach
to the phomactins was envisaged in which a [2,3]-Wittig rear-
rangement of a lithiated 1-(alk-2-yn-1-yloxymethyl)cyclohexene,
e.g., 13, would be used to prepare a 2-(1-hydroxyalk-2-yn-1-yl)-1-
methylenecyclohexane 14, see Scheme 2. Further modification, e.g.,
2. Discussion
The synthesis and Wittig rearrangement of the propargyl ether
25 is outlined in Scheme 3. Using lithium rather than sodium, re-
ductive methylation11 of o-toluic acid 16 followed by esterification
Me
Me
Me
Me
Me
6
i, ii
MeO2C
PO
HO2C
MeO2C
Me
Br
OTBDPS
28
iv
OTBDPS
i - iii
29 P = THP
30 P = H
X
O
O
16
17 X = H2
18 X = O
19
iii
+
O
O
O
Br
Br
O
Me
Me
TBDPSO
Me
TBDPSO
Me
Me
6
Me
MeO2C
MeO2C
MeO2C
Me
MeO2C
Me
PO
vi
v
iv, v
O
O
O
Me
32 P = H
Me
Me
O
O
31
21
20
22
33 P = TBS
vii
Me
Me
vi
OH
O
O
O
O
Me
H
Me
H
O
Me
Me
TBSO
MeO2C
Me
TBSO
vii
PO
viii, ix
O
O
O
O
Me
Me
O
Me
O
24 P = H
25 P = TBS
23
35a,b
TBDPSO
TBDPSO
O
34
viii
viii
x
Me
OH
OTBDPS
O
Me
Me
H
O
Me
H
TBSO
1'
O
TBSO
Me
TBSO
2
xi
2
O
Me
HO
Me
Me
O
Me
Me
O
Me
O
27
26
TBDPSO
37
36
Scheme 3. Reagents and conditions (i) (a) Li, liq. NH3, THF, ꢀ78 ꢁC, then MeI (99%); (ii)
SOCl2, MeOH, reflux, 1 h (98%); (iii) tBuOOH, PDC, benzene, 0 ꢁC, 3.5 h (68%); (iv) MeLi,
CuI, ether, 0 ꢁC, 30 min, add 18, 30 min (89%: 19/20¼23:77); (v) NBS, AIBN (trace), CCl4,
reflux, 24 h (21; 67%); (vi) ethylene glycol, PPTS, benzene, reflux, Dean–Stark (95%);
(vii) but-2-ynol, NaH, THF, rt, 30 min, add 22, rt, 24 h (53%); (viii) LiEt3BH, THF, 0 ꢁC, 1 h
Scheme 4. Reagents and conditions: (i) THPOCH2CCH, nBuLi, THF, 0 ꢁC, 30 min, add 28,
THF, reflux, 16 h (99%); (ii) PPTS, MeOH, rt, 2 days (58%); (iii) NaH, THF, reflux 1 h, add
21, THF, reflux, 5 h (50%); (iv) LiEt3BH, THF, 0 ꢁC, 30 min (91%); (v) TBSCl, imid., DCM, rt,
44 h (80%); (vi) nBuLi, ꢀ78 ꢁC, 3 h (82%; two isomers, 67:33); (vii) DMSO, (COCl)2, DCM,
3 h, Et3N, rt, 9 h (35a, 28%; 35b, 42%); (viii) aq HCl (10%), acetone, H2O, rt (36, 46%; 37,
44%).
n
(80%); (ix) TBSOTf, Et3N, DCM, rt, 6 h (67%); (x) BuLi, THF, ꢀ78 ꢁC, 3 h (50%; two
isomers, 70:30); (xi) DMSO, (COCl)2, DCM, ꢀ78 ꢁC, 3 h, Et3N, rt, 2 h (65%; 70:30).

P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
4203
considerations of steric interactions in the transition structures for
Wittig rearrangements of ether 25 indicated the likely preferred
relative configurations at C(2) and C(10) in the rearrangement
products 26,15 these were not confirmed.16 Instead [2,3]-Wittig
rearrangements of substrates with more developed side-chains
were investigated.
O
Me
TBDPSO
i
33
TBSO
Me
O
38
ii
The tetrahydropyranyl ether of prop-2-ynol was alkylated using
bromide 28 to give alkyne 29, which was deprotected selectively to
give the hexynol 30. This was alkylated using bromide 21 to give the
propargylic ether 31, which was reduced and the resulting primary
alcohol 32 protected as its tert-butyldimethylsilyl ether 33. The
Wittig rearrangement was carried out using n-butyllithium and
gave a good yield, 82%, of a mixture of two inseparable stereoiso-
mers of the propargylic alcohol 34, ratio 67:33. Oxidation of this
mixture under Swern conditions gave a mixture of the two ketones
35a,b, 70% combined yield, which could be separated. As before,
considerations of likely steric interactions in the transition struc-
tures of the Wittig rearrangements of ether 33 indicated the likely
relative configurations at C(2) and (10), but these were not con-
firmed although preliminary NMR data did indicate the probable
stereochemistry at C(2).17
O
O
Me
TBDPSO
Me
TBDPSO
+
TBSO
TBSO
Me
OTES
Me
OTES
40
39
iii
.
Li
Me
O
HO
Me
OTBDPS
TBDPSO
via
TBSO
Me
TBSO
OTES
Me
O
42
41a,b
Attempts to hydrolyse the acetal protecting group of the mix-
ture of rearrangement products 34 was accompanied by de-
hydration and deprotection giving the hydroxydienone 36, the
geometry of the exocyclic double-bond being provisionally
assigned by the lack of an NOE enhancement of either of the
methylene protons on irradiation of H(10).18 Hydrolysis of the major
keto-acetal 35b led to migration of the exocyclic double-bond and
gave the conjugated diketone 37, cf. the formation of enedione 12
(Scheme 4).10
Scheme 5. Reagents and conditions: (i) PPTS, acetone–H2O, reflux, 3 h (92%); (ii)
n
Et3SiOTf, Et3N, DCM, rt, 21 h (40, 10%; 39, 69%); (iii) BuLi, THF, ꢀ78 ꢁC, 2 h (41a, 25%;
41b, 25%).
gave methyl 1,2-dimethylcyclohexa-2,5-diene-1-carboxylate 17,
and allylic oxidation to the ketone 18 was carried out using pyr-
idinium dichromate and tert-butyl hydroperoxide.12
Preliminary studies of free-radical bromination of the 2-methyl
group of dienone 18 were complicated by bis-bromination, and
conversion of dienone 18 into methyl 2-hydroxymethyl-1-methyl-
4-oxocyclohexa-2,5-diene-1-carboxylate by oxidation of the exo-
cyclic double-bond of its tert-butyldimethylsilyl dienol ether using
dimethyl dioxirane13 was difficult to scale up. However, conjugate
addition14 of lithium dimethylcuprate to dienone 18 was found to
be regioselective for the less substituted double-bond and was
stereoselective in favour of diastereoisomer 20 in which the two
methyl groups were cis-disposed about the six-membered ring,
19:20¼23:77 (89% combined yield). The structure of the major
isomer 20 was established by X-ray crystallography, see Figure 1.
Although the stereoselectivity of this conjugate addition was
only modest, the major isomer 20 had the relative stereochemistry
at its two stereogenic centres corresponding to that at C(11) and
C(12) of the phomactins. Preliminary studies of the analogous
conjugate addition using the isopropyl ester corresponding to 18, or
by using different reaction solvents, did not reveal significant im-
provements in the stereoselectivity, and so the conjugate addition
of lithium dimethylcuprate to the dienone 18 was retained for the
preparation of ester 20, although, for convenience, a mixture of the
epimers 19 and 20 was taken through to the next step.
O
Me
TBDPSO
i, ii
38
TBSO
Me
OP
43 P = H
44 P = TIPS
iii
OH
OH
Me
H
H
Me
H
H
TBSO
TBSO
+
Me
OTIPS
Me
OTIPS
46
45a,b TBDPSO
TBDPSO
iv
v
O
O
Me
H
H
Me
H
H
TBSO
TBSO
Me
OTIPS
Me
OTIPS
Allylic bromination of the mixture of epimeric esters 19 and 20
was carried out using N-bromosuccinimide and the required bro-
momethyl ester 21 was isolated from the mixture of products in
a 67% yield based on the amount of ester 20 in the starting material.
Following protection of the ketone 21 as its acetal 22, which was
found to be rather unstable, displacement of the bromide using the
sodium salt of but-2-ynol gave ether 23 (53%). Reduction of
the methoxycarbonyl group was then carried out using lithium
triethylborohydride and the alcohol 24 was protected as its tert-
butyldimethylsilyl ether 25.
TBDPSO
TBDPSO
48
vi
47
vi
O
O
H
Me
H
Me
H
TBSO
TBSO
H
Me
Me
Me
Me
OTIPS
OTIPS
TBDPSO
TBDPSO
50
49
The Wittig rearrangement of ether 25 using n-butyllithium gave
a mixture of only two of the four possible stereoisomers of the
homoallylic alcohol 26 (50%), and oxidation of this mixture gave
a mixture of both epimeric ketones 27, ratio 70:30, showing the two
alcohols had the opposite configuration at C(2). Although
Scheme 6. Reagents and conditions: (i) NaBH4, CeCl3$7H2O, MeOH, rt, 1 min (98%); (ii)
n
TIPSCl, imid., DCM, rt, 46 h (99%); (iii) BuLi, THF, ꢀ78 ꢁC, 4 h (45a, 29%; 45b, 19%; 46,
21%); (iv) TPAP, 45a, NMO, 4 Å sieves, DCM, rt, 70 h (77%); (v) DMSO, (COCl)2, DCM, 46,
ꢀ78 ꢁC, 7 h, Et3N, 14 h (81%); (vi) MeLi, CuI, Et2O, 0 ꢁC, 30 min, add 47 or 48, 30 min
[(Z)-49, 50%; (E)-49, 49%; (Z)-50, 35%; (E)-50, 57%).

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P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
O
O
O
O
O
O
O
CHO
Me
Me
P1O
Me
Me
i - iv
v
vi
33
P2O
TBSO
TBSO
CO2Et
O
O
O
Me
Me
Me
O
59
60
55 P1 = P2 = H
56 P1 = Bz, P2 = H
57 P1 = Bz, P2 = TBS
58 P1 = H, P2 = TBS
vii - ix
O
O
Me
Me
Me
Me
x, xi
P2O
X
OP1
OTBS
O
O
Me
Me
61 P1 = H, P2 = TBS
62 P1 = P2 = H
63 P1 = TBS, P2 = H
64 X = PhS
65 X = PhS(O)2
Scheme 7. Reagents and conditions: (i) TBAF, THF, rt, 1 h (94%); (ii) PhCOCl, Et3N, DCM, 0 ꢁC, 1 h, rt, 16 h (89%); (iii) TBSCl, imid., DCM, rt, 51 h (55%); (iv) NaOH, H2O, MeOH, rt,
90 min (97%); (v) NMO, 4 Å sieves, DCM, 58, rt, 30 min, add TPAP, 30 min (70%); (vi) Ph3P]C(Me)CO2Et, DCM, rt, 12 h (80%); (vii) LiEt3BH, THF, 0 ꢁC, 30 min (98%); (viii) TBAF, THF, rt,
5 h (75%); (ix) TBSCl, imid., DCM, rt, 14 h (84%); (x) (a) MsCl, py, rt, 20 h (b) PhSH, NaH, DMF, 60 ꢁC, 26 h (79%); (xi) DMDO, acetone, rt, 30 min (50%).
To avoid the complications due to the dehydration and iso-
merisation observed during hydrolysis of the acetals 34 and 35b, it
was decided to look at [2,3]-Wittig rearrangements of other de-
rivatives of the ketone 38 prepared by hydrolysis of acetal 33 (92%).
Reaction of the ketone with triethylsilyl trifluoromethanesulfonate
in the presence of triethylamine gave mainly the cross-conjugated
enol ether 39 although a small amount of its separable regioisomer
40 was also formed. However, the [2,3]-Wittig rearrangement of
enol ether 39 with an acidic work-up, proceeded with the un-
wanted regioselectivity via the lithiated ether 42 and gave the
allenes 41 as a mixture of epimers (50%), see Scheme 5.
epoxidation of the mixture of rearrangement products 34 gave
a complex mixture of epoxides 51, and attempts to hydrolyse the
acetal, in some cases after preparation of the 10-benzoate 52, led to
decomposition. Single isomers of the keto-epoxides 53 and 54 were
prepared from the alcohols 45a and 46 followed by oxidation, but
attempts to isomerise these under basic conditions to give the
corresponding conjugated allylic alcohols either led to returned
starting material (triethylamine, LDA) or decomposition (DBU).
OR
O
Me
H
TBSO
O
Ketone 38 was therefore reduced under Luche conditions to
give alcohol 43 as a single diastereoisomer. The configuration of
the alcohol at C(1) was initially assigned on the basis that the
incoming hydride would approach the ketone on its less hindered
face away from the axial methyl group at C(4), and was sub-
sequently confirmed by later work.16 Following protection of the
alcohol as its tri-isopropylsilyl ether 44, the Wittig rearrangement
was found to give the three diastereoisomeric products 45a,b and
46. In these cases the configurations of the products at C(2) were
assigned on the basis of the diaxial coupling, ca. 10 Hz, observed
between H(2) and H(3) for products 45a,b, the analogous coupling
for isomer 46 being ca. 4.5 Hz. The configurations of the products
at C(10) were not formally established but could be tentatively
assigned on the basis of likely steric interactions in the transition
structures for the rearrangements.19 Oxidation of alcohols 45a and
b gave the same ketone 47, whereas alcohol 46 gave the epimeric
ketone 48.
At this stage, preliminary studies were carried out into the re-
actions of the conjugated ynones 47 and 48 with lithium dime-
thylcuprate to see whether this procedure could be used for the
preparation of intermediates with a conjugated trisubstituted (E)-
double-bond corresponding to the C(20)-C(30) double-bond present
in potential precursors of the phomactins. However, reactions of
ketones 47 and 48 with lithium dimethylcuprate gave rise to
mixtures of (20E)- and (20Z)-enones 49 and 50 (82–99%). Surpris-
ingly, subsequent isomerisation with iodine gave predominantly
the (20Z)-isomer, (20-Z)-49, from the (E,Z)-mixture 49 and the
(20E)-isomer, (20-E)-50, from the (E,Z)-mixture 50. The origin of this
dichotomy was not investigated (Scheme 6).
Me
51 R = H
52 R = Bz
O
TBDPSO
TBSO
O
O
O
O
Me
H
Me
H
TBSO
Me
OTIPS
Me
OTIPS
H
H
54
53
TBDPSO
TBDPSO
Finally, the Wittig precursor 33 was modified to prepare a more
advanced intermediate 65, see Scheme 7. Desilylation followed by
selective benzoylation of the more accessible hydroxyl group in the
side-chain, protection of the 8-hydroxymethyl group as a tert-
butyldimethylsilyl ether, and saponification of the ester gave
alcohol 58, which was oxidised to the aldehyde 59. A Wittig
condensation of this aldehyde and reduction of the resulting ester
60 then gave the alcohol 61, which on deprotection gave diol 62.
Selective protection of the more accessible hydroxyl group pro-
vided the alcohol 63, which was taken through to the sulfone 65 by
displacement of the corresponding mesylate followed by oxidation.
Sulfone 65 corresponds to the sulfone 13 identified as a possible
precursor of the phomactins, see Scheme 2.
3. Conclusions
This work provided results, which have underpinned a synthetic
approach to phomactins. The usefulness of [2,3]-Wittig rear-
rangements for the synthesis of suitably substituted methyl-
enecyclohexanes has been confirmed and stereoselective syntheses
of Wittig rearrangement precursors, i.e., the propargylic ethers 44
and 65, which have the functionality required for incorporation
into a phomactin, have been developed. However, more efficient
syntheses of Wittig rearrangement precursors with fully developed
During the course of this work, preliminary studies were carried
out on the epoxidation of the exocyclic methylene groups of the
Wittig rearrangement products 34 and 45 with a view to sub-
sequent isomerisation to introduce the C(1)–C(15) double-bond
and the hydroxyl group at C(20) of the phomactins. However,

P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
4205
side-chains, i.e., sulfones 13 and 65, and control of the stereo-
4.3. Methyl 1,2-dimethyl-4-oxocyclohexa-2,5-diene-1-
carboxylate 18
selectivity of the Wittig rearrangements, were required before this
work could be incorporated into a stereoselective synthesis of
phomactins. Both of these problems have been overcome and this
approach has now been used to prepare macrocyclic precursors of
the phomactins.16,18
An aqueous solution of tert-butyl hydroperoxide (70% w/v,
47 cm3, 0.345 mol) was added dropwise at 0 ꢁC to a mechanically
stirred mixture of diene 17 (19.08 g, 0.115 mol), pyridinium di-
chromate (129.7 g, 0.345 mol) and CeliteÒ (48 g) in benzene
(500 cm3). After 3.5 h, the mixture was filtered and the solids were
washed with ether (5ꢂ200 cm3). The extracts were concentrated to
w200 cm3 then washed with saturated aqueous sodium meta-
bisufite (200 cm3) and brine (200 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether/light petroleum (1:8 to 2:3) gave
the title compound 18 (14.09 g, 68%) as a pale yellow solid. An an-
alytical sample was crystallised from ether at ꢀ78 ꢁC, mp 52.6–
53.6 ꢁC (ether); Rf¼0.1 (10% ether in light petroleum) (found: C,
66.98; H, 7.01%; Mþ, 180.0788; C10H12O3 requires C, 66.65; H, 6.71%;
M, 180.0876); nmax/cmꢀ1 1738, 1667, 1438, 1227, 1104 and 888; dH
6.82 (1H, d, J 10, 6-H), 6.34 (1H, dd, J 10, 1, 5-H), 6.22 (1H, qn, J 1, 3-
H), 3.73 (3H, s, 1-CO2CH3), 2.02 (3H, d, J 1, 2-CH3) and 1.56 (3H, s, 1-
CH3); dC 185.6, 170.9, 157.6, 148.7, 128.7, 128.3, 53.1, 51.5, 22.2 and
20.2; m/z (CI) 198 (Mþþ18, 14%), 181 (100), 136 (8) and 121 (7); m/z
(EI) 180 (Mþ, 35%), 136 (30), 121 (100), 91 (96), 77 (92) and 49 (92).
4. Experimental section
4.1. General procedures
Melting points were recorded on a Gallenkamp apparatus.
Proton NMR spectra were recorded using Varian Unity A300 and
500 spectrometers. Coupling constants are given in hertz and
chemical shifts relative to Me4Si. IR spectra were recorded on
a Perkin Elmer 1710FT spectrometer and were run as liquid films,
KBr discs or as solutions in chloroform. Low resolution mass spectra
were measured on a Micromass Trio 200 spectrometer and high
resolution spectra on a Kratos Concept IS spectrometer.
Chromatography refers to flash chromatography using Merck
silica gel 60H (40–63 nm3, 230–400 mesh). Light petroleum refers
to the fraction boiling at 40–60 ꢁC and ether to diethyl ether. All
solvents and reagents were purified by standard techniques before
use and all non-aqueous reactions were performed under an at-
mosphere of dry argon or nitrogen.
4.4. Methyl (1RS,6RS)- and (1RS,6SR)-1,2,6-trimethyl-4-
oxocyclohex-2-ene-1-carboxylates 19 and 20
4.2. Methyl 1,2-dimethylcyclohexa-2,5-diene-1-carboxylate 17
Methyllithium (1.6 M in ether, 100 cm3, 0.16 mol) was added to
a suspension of copper(I) iodide (17.65 g, 0.093 mol) in ether
(180 cm3) at 0 ꢁC. After 30 min, a solution of dienone 18 (11.72 g,
0.065 mol) in ether (80 cm3) was added dropwise. After 30 min,
a mixture of concentrated aqueous ammonia and saturated aque-
ous ammonium chloride (1:1, 500 cm3) was added. The blue
aqueous layer was extracted with ether (3ꢂ200 cm3). The extracts
were washed with water (250 cm3), brine (250 cm3), dried
(MgSO4), filtered and concentrated under reduced pressure. Chro-
matography of the residue on silica eluted with ether/light petro-
leum (1:4) gave the title compounds 19 and 20 (9.02 g, 89%;
19:20¼23:77). The two diastereoisomers were separated by HPLC
to yield first the (1RS,6SR)-isomer of the title compound 20 as a col-
ourless solid, mp 63–65 ꢁC (light petroleum/ether); Rf¼0.3 (50%
ether in light petroleum) (found: Mþ, 196.1093; C11H16O3 requires
M, 196.1099); nmax/cmꢀ1 2959, 1737, 1667, 1628, 1248, 1192, 1118 and
1013; dH 5.93 (1H, s, 3-H), 3.79 (3H, s, 1-CO2CH3), 2.77 (1H, m, 6-H),
2.42 (1H, dd, J 17, 4, 5-H), 2.23 (1H, dd, J 17, 13, 5-H0), 1.91 (3H, s, 2-
CH3), 1.32 (3H, s, 1-CH3) and 0.97 (3H, d, J 7, 6-CH3); dC 197.8, 174.8,
162.7, 127.2, 52.4, 52.3, 40.9, 35.9, 20.4, 16.4 and 14.6; m/z (CI) 214
(Mþþ18, 100%) and 197 (73); m/z (EI) 196 (Mþ, 17%), 154 (32), 109
(56), 86 (100), 84 (100) and 49 (100). The second fraction was the
(1RS,6RS)-isomer of the title compound 19 isolated as a colourless
solid, mp 55–56.5 ꢁC (light petroleum/ether); (found Mþ, 196.1095;
C11H16O3 requires M, 196.1099); nmax/cmꢀ1 2954, 1730, 1671, 1629,
1438, 1237, 1167, 1106 and 1015; dH 5.99 (1H, s, 3-H), 3.75 (3H, s,
1-CO2CH3), 2.60 (1H, dd, J 17, 13, 5-H0), 2.36 (1H, dd, J 17, 4, 5-H),
2.20 (1H, m, 6-H), 1.94 (3H, s, 2-CH3), 1.46 (3H, s, 1-CH3) and 1.05
(3H, d, J 7, 6-CH3); dC 198.6, 172.5, 160.3, 128.4, 52.1, 51.5, 42.1, 38.2,
21.3, 21.1 and 16.9; m/z (CI) 214 (Mþþ18, 100%) and 197 (94); m/z
(EI) 196 (Mþ, 31%), 154 (30), 109 (59), 83 (100) and 67 (60).
o-Toluic acid (30.19 g, 0.22 mol) was dissolved in tetrahydro-
furan (50 cm3) and liquid ammonia (w600 cm3), freshly distilled
from sodium, at ꢀ78 ꢁC. Lithium was added in portions until
a
blue colour persisted for 15 min. Iodomethane (27.6 cm3,
0.44 mol) was added dropwise. After 90 min, the cooling bath was
removed and the ammonia was allowed to evaporate overnight.
The white residue was dissolved in water (400 cm3) and acidified
with concentrated hydrochloric acid. The aqueous solution was
extracted with ether (3ꢂ400 cm3). The extracts were washed with
brine (2ꢂ500 cm3), dried (MgSO4), filtered and concentrated un-
der reduced pressure to yield 1,2-dimethylcyclohexa-2,5-diene-1-
carboxylic acid (33.25 g, 99%) as a yellow solid. An analytical
sample was recrystallised from light petroleum to yield a colour-
less solid. Mp 64–65 ꢁC (light petroleum) (found: Mþ, 152.0835;
C9H12O2 requires M, 152.0837); nmax/cmꢀ1 3310, 1710, 1256 and
840; dH 10.65 (1H, br s, CO2H), 5.89 (1H, dtd, J 10, 3, 1, 5-H), 5.64
(2H, m, 3-H and 6-H), 2.83–2.62 (2H, m, 4-H2), 1.79 (3H, d, J 1, 2-
CH3) and 1.40 (3H, s, 1-CH3); dC 181.0, 132.7, 128.9, 125.2, 121.7,
47.4, 26.7, 23.6 and 19.6; m/z (EI) 152 (Mþ, 5%), 107 (100) and 91
(85).
A solution of the acid (33.25 g, 0.22 mol) in thionyl chloride
(160 cm3, 2.2 mol) was heated under reflux for 1 h. After cooling
to ambient temperature, the excess thionyl chloride was re-
moved under reduced pressure. Methanol (200 cm3) followed
by triethylamine (61 cm3, 0.43 mol) was added slowly at 0 ꢁC.
After 30 min, water (100 cm3) was added and the mixture
extracted with ether (3ꢂ200 cm3). The extracts were washed
with brine (200 cm3), dried (MgSO4), filtered and concentrated
under reduced pressure to yield the title compound 17 (35.53 g,
98%) as a yellow liquid. An analytical sample was distilled to
yield the ester 17 as a colourless liquid. Bp 58–60 ꢁC (1.5 mmHg);
Rf¼0.65 (10% ether in light petroleum) (found: Mþ, 166.0994;
C10H14O2 requires M, 166.0994); nmax/cmꢀ1 1732, 1436, 1232,
1102 and 706; dH 5.84 (1H, dtd, J 10, 3, 1, 5-H), 5.60 (2H, m, 3-H
and 6-H), 3.71 (3H, s, 1-CO2CH3), 2.73 (2H, m, 4-H2), 1.72 (3H, d, J
1, 2-CH3) and 1.38 (3H, s, 1-CH3); dC 175.2, 133.2, 129.3, 124.4,
121.1, 52.2, 47.1, 26.7, 23.9 and 19.6; m/z (CI) 166 (Mþ, 9%), 107
(100) and 91 (71).
4.5. Methyl (1RS,6SR)-2-(bromomethyl)-1,6-dimethyl-4-
oxocyclohex-2-ene-1-carboxylate 21
2,20-Azobis(2-methylpropionitrile) (0.45 g, 2.73 mmol) and N-
bromosuccinimide (5.35 g, 30.1 mmol) were added to a solution of
a mixture of enones 19 and 20 (19/20¼25:75; 5.36 g, 27.3 mmol) in
degassed (N2 flow; 30 min) carbon tetrachloride (125 cm3). The

4206
P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
mixture was heated under reflux for 24 h, cooled to ambient tem-
perature and filtered. The filtrate was concentrated under reduced
pressure. Chromatography of the residue on silica eluted with ether
in light petroleum (1:6 to 1:5) gave the title compound 21 (3.75 g,
67%) as a yellow liquid, Rf¼0.4 (50% ether in light petroleum)
and 10-H2), 3.71 (3H, s, 8-CO2CH3), 2.56 (1H, m, 9-H), 1.87 (3H, m, 40-
H3), 1.74 (2H, m, 10-H2), 1.22 (3H, s, 8-CH3) and 0.89 (3H, d, J 7, 9-
CH3); dC 175.5, 142.1, 124.7, 105.4, 82.5, 74.8, 68.9, 64.7, 64.4, 57.8,
52.0, 49.6, 37.4, 34.4, 16.3, 14.6 and 3.5; m/z (CI) 326 (Mþþ18, 11%)
and 309 (Mþþ1, 100).
(found: MþþH, 275.0285; C11H16O739Br requires M, 275.0283); nmax
/
cmꢀ1 2955,1732, 1676,1628,1453,1251, 1191, 1116 and 1013; dH 6.21
(1H, s, 3-H), 4.00 (1H, d, J 12, 2-CH), 3.88 (1H, d, J 12, 2-CH0), 3.70
(3H, s, 1-CO2CH3), 2.67 (1H, m, 6-H), 2.38 (1H, dd, J 17.5, 4.5, 5-H),
2.20 (1H, dd, J 17.5, 11.5, 5-H0), 1.36 (3H, s, 1-CH3) and 0.90 (3H, d, J 7,
6-CH3); dC 197.6, 174.0, 158.7, 130.2, 52.7, 51.8, 41.3, 36.6, 29.8, 16.3
and 16.0; m/z (CI) 294 (Mþþ18, 100%), 292 (Mþþ18, 92), 277 (Mþ,
37), 275 (Mþ, 35), 214 (34), 197 (35) and 195 (39).
4.8. (8RS,9SR)-7-(But-2-ynyloxy)methyl-8,9-dimethyl-8-
hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene 24
A solution of lithium triethylborohydride (1.0 M in tetrahydro-
furan, 2.73 cm3, 2.73 mmol) was added dropwise at 0 ꢁC to a solu-
tion of the ester 23 (382 mg, 1.24 mmol) in tetrahydrofuran (4 cm3).
After 1 h, the reaction was poured into water/ether (1:1) and the
aqueous layer was extracted with ether (2ꢂ6 cm3). The extracts
were washed with brine (10 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether in light petroleum (2:1) gave the
title compound 24 (278 mg, 80%) as a colourless liquid, Rf¼0.15 (50%
ether in light petroleum) (found: MþþH, 281.1755; C16H25O4 re-
quires M, 281.1753); nmax/cmꢀ1 3484, 2961, 2222, 1665, 1357, 1177,
1096, 1069 and 965; dH 5.70 (1H, s, 6-H), 4.16–3.28 (10H, m, 2-H2, 3-
H2, 7-CH2O, 10-H2 and 8-CH2O), 2.72 (1H, dd, J 10 and 5, 8-CH2OH),
2.35 (1H, m, 9-H), 1.79 (3H, t, J 2, 40-CH3), 1.66 (2H, m, 10-H2), 0.86
(3H, d, J 7, 9-CH3) and 0.70 (3H, s, 8-CH3); dC 143.8,132.4,105.2, 83.3,
74.2, 70.5, 64.7, 64.6, 64.4, 58.3, 43.1, 37.7, 30.1, 15.4, 14.8 and 3.5; m/
z (CI) 298 (Mþþ18, 4%), 282 (19), 281 (100) and 181 (69).
4.6. Methyl (8RS,9SR)-7-(bromomethyl)-8,9-dimethyl-1,4-
dioxaspiro[4.5]dec-6-ene-8-carboxylate 22
Ethylene glycol (4.45 cm3, 79.85 mmol) was added to a solution
of the ketobromide 21 (5.49 g, 19.96 mmol) and pyridinium tolu-
ene-4-sulfonate (0.50 g, 2.00 mmol) in benzene (60 cm3) and the
mixture was heated under reflux in a Dean–Stark apparatus for
14 h. After cooling to ambient temperature, the benzene was re-
moved under reduced pressure below 30 ꢁC. The residue was taken
up in ether (100 cm3) and the ethereal solution was washed with
saturated aqueous sodium bicarbonate (50 cm3), water (50 cm3),
brine (50 cm3), dried (MgSO4), filtered and concentrated under
reduced pressure below 30 ꢁC to yield the acetal 22 (6.05 g, 95%) as
a yellow liquid. Chromatography of a sample on silica eluted with
ether in light petroleum (8:1) gave the title compound 22 as a col-
ourless liquid, Rf¼0.2 (20% ether in light petroleum) (found: MþþH,
319.0552; C13H20O749Br requires M, 319.0545); nmax/cmꢀ1 2995,
1730, 1665, 1453, 1252, 1147, 1084, 1026 and 969; dH 5.83 (1H, s, 6-
H), 4.06 (4H, m, 2-H2 and 3-H2), 3.97 (1H, d, J 11.5, 7-CH), 3.81 (1H,
d, J 11.5, 7-CH0), 3.76 (3H, s, CO2CH3), 2.60 (1H, m, 9-H), 1.77 (2H, m,
10-H2), 1.30 (3H, s, 8-CH3) and 0.93 (3H, d, J 7, 9-CH3); dC 175.1, 141.7,
129.8, 105.1, 64.8, 64.5, 52.3, 51.2, 37.0, 34.5, 30.7, 16.3 and 15.1; m/z
(CI) 338 (Mþþ18, 24%), 336 (26), 321 (89) and 319 (100); m/z (EI)
319 (Mþ, 3%), 239 (100), 197 (37) and 179 (54).
Methyl (8RS,9SR)-7-[1-bromomethylidene]-8,9-dimethyl-1,4-
dioxaspiro[4.5]decane-8-carboxylate (10%) was also isolated from
the column (found: MþþH, 319.0545; C13H20O749Br requires M,
319.0545); nmax/cmꢀ1 2953, 1729, 1455, 1242, 1133, 1102 and 1078;
dH 5.82 (1H, d, J 1.5, 7-CHBr), 4.02–3.84 (4H, m, 2-H2 and 3-H2), 3.67
(3H, s, 8-CO2CH3), 2.83 (1H, dd, J 14.5, 2, 6-H), 2.49 (1H, m, 9-H),
2.31 (1H, d, J 14.5, 6-H0), 1.64 (2H, m, 10-H2), 1.19 (3H, s, 8-CH3) and
0.78 (3H, d, J 7, 9-CH3); dC 175.3, 142.8, 108.1, 103.6, 64.6, 64.5, 54.6,
52.1, 39.0, 37.0, 34.8, 16.4 and 16.3; m/z (CI) 338 (Mþþ18, 26%), 336
(Mþþ18, 28), 321 (Mþþ1, 100), 319 (Mþþ1, 91) and 239 (79).
4.9. (8RS,9SR)-8-(tert-Butyldimethylsilyloxymethyl)-7-(but-
2-ynyloxy)methyl-8,9-dimethyl-1,4-dioxaspiro-[4.5]dec-
6-ene 25
Triethylamine (0.17 cm3, 1.184 mmol) followed by tert-butyldi-
methylsilyl trifluoromethanesulfonate (0.20 cm3, 0.868 mmol) was
added to a solution of the alcohol 24 (221 mg, 0.789 mmol) in
dichloromethane (2.5 cm3). After 6 h, the reaction was diluted with
dichloromethane (5 cm3), washed with saturated aqueous sodium
bicarbonate (5 cm3) then concentrated under reduced pressure.
The residue was taken up in ether (25 cm3) and the mixture fil-
tered. The filtrate was passed through a plug of anhydrous MgSO4
and concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether in light petroleum (1:20 to 1:4)
gave the title compound 25 (206 mg, 67%) as a colourless liquid,
Rf¼0.85 (50% ether in light petroleum) (found: Mþ, 394.2527;
C22H38O4Si requires M, 394.2539); nmax/cmꢀ1 2954, 1671, 1466,
1360, 1254, 1099, 1074, 840 and 776; dH 5.63 (1H, d, J 1, 6-H), 4.15–
3.80 (8H, m, 2-H2, 3-H2, 7-CH2 and 10-H2), 3.51 (1H, d, J 10.5, 8-CH),
3.40 (1H, d, J 10.5, 8-CH0), 2.20 (1H, m, 9-H), 1.81 (3H, t, J 2, 40-H3),
1.72 (2H, m, 10-H2), 0.84 (12H, m, SiC(CH3)3 and 9-CH3), 0.80 (3H, s,
8-CH3) and 0.00 [6H, s, Si(CH3)2]; dC 144.8, 124.4, 105.6, 82.1, 75.2,
69.4, 65.2, 64.4, 64.2, 57.7, 42.1, 37.9, 30.8, 25.8, 18.1, 15.3, 14.9, 3.5,
ꢀ3.7 and ꢀ5.7; m/z (EI) 394 (Mþ, 3%), 193 (22), 83 (80) and 73 (100).
4.7. Methyl (8RS,9SR)-7-(but-2-ynyloxy)methyl-8,9-dimethyl-
1,4-dioxaspiro[4.5]dec-6-ene-8-carboxylate 23
But-2-ynol (0.274 cm3, 3.67 mmol) was added dropwise to
a suspension of sodium hydride (60% dispersion in mineral oil,
147 mg, 3.67 mmol) in tetrahydrofuran (10 cm3) followed, after
30 min, by the bromide 22 (390 mg, 1.22 mmol) in tetrahydrofuran
(5 cm3). After 24 h, saturated aqueous ammonium chloride
(15 cm3) was added. The layers were separated and the aqueous
layer was extracted with ether (2ꢂ15 cm3). The extracts were
washed with water (15 cm3), brine (15 cm3), dried (MgSO4), filtered
and concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether in light petroleum (1:4) gave the
title compound 23 (201 mg, 53%) as a yellow liquid, Rf¼0.15 (20%
ether in light petroleum) (found: Mþ, 308.1624; C17H24O5 requires
M, 308.1624); nmax/cmꢀ1 2953, 1730, 1669, 1437, 1252, 1145, 1103
and 1074; dH 5.74 (1H, s, 6-H), 4.09–3.89 (8H, m, 2-H2, 3-H2, 7-CH2
4.10. (8RS,9SR)-8-(tert-Butyldimethylsilyloxymethyl)-6-(1-
hydroxybut-2-ynyl)-8,9-dimethyl-7-methylene-1,4-
dioxaspiro[4.5]decane 26
n-Butyllithium (1.6 M in hexanes; 1.06 cm3, 1.698 mmol) was
added dropwise at ꢀ78 ꢁC to a solution of the ether 25 (134 mg,
0.340 mmol) in tetrahydrofuran (2.5 cm3). After 3 h, saturated
aqueous ammonium chloride (3 cm3) was added and the aqueous
layer was extracted with ether (2ꢂ4 cm3). The extracts were
washed with brine (10 cm3), dried (MgSO4), filtered and concen-
trated under reduced pressure. Chromatography of the residue on
silica eluted with ether in light petroleum (1:3) gave the title
compound 26 (68 mg, 50%), a 70:30 mixture of diastereoisomers, as
a colourless liquid, Rf¼0.4 (50% ether in light petroleum) (found:

P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
4207
MþþH, 395.2626; C22H39O4Si requires M, 395.2617); nmax/cmꢀ1
3507, 2954, 2229, 1639, 1467, 1254, 1096, 1034, 840 and 776; dH 5.77
(0.7H, s, 7-CH), 5.44 (0.3H, s, 7-CH), 5.22 (0.3H, s, 7-CH0), 5.19 (0.7H,
s, 7-CH0), 4.95 (0.7H, m, 10-H), 4.81 (0.3H, m, 10-H), 3.98 (4H, m, 2-H2
and 3-H2), 3.63 (0.3H, s, 10-OH), 3.54 (0.7H, m, 10-OH), 3.48 (2H, m,
8-CH2), 2.82 (0.7H, br s, 6-H), 2.79 (0.3H, m, 6-H), 2.00 (1H, m, 9-H),
1.82 (0.9H, d, J 2.3, 40-H3), 1.79 (2.1H, d, J 2.3, 40-H3), 1.77–1.49 (2H,
m, 10-H2), 0.95 (2.1H, s, 8-CH3), 0.86 [12.9H, m, 8-CH3, 9-CH3 and
SiC(CH3)3], 0.04 [1.8H, s, Si(CH3)2], 0.00 [4.2H, s, Si(CH3)2]; dC 146.5,
145.0, 114.4, 112.8, 112.3, 111.0, 80.6, 80.4, 79.7, 79.2, 69.8, 67.6, 65.8,
64.4, 64.3, 64.0, 63.8, 61.3, 61.0, 52.4, 51.2, 45.0, 44.0, 39.7, 38.5, 32.0,
30.7, 25.8, 25.8, 18.7, 18.2, 16.8, 16.0, 15.6, 15.2, 3.8, ꢀ5.6 and ꢀ5.7;
m/z (CI) 412 (Mþþ18, 2%), 395 (6), 391 (27), 377 (42), 327 (100) and
283 (24).
2.59 (1H, m, 9-H), 2.40 (2H, tt, J 7.5, 2, 40-H2),1.76 (4H, m,10-H2 and
50-H2), 1.22 (3H, s, 8-CH3), 1.08 [9H, s, SiC(CH3)3] and 0.90 (3H, d, J
7, 9-CH3); dC 175.5, 142.1, 135.5, 133.7, 129.5, 127.6, 124.8, 105.4,
86.7, 75.7, 68.9, 65.8, 64.7, 64.4, 62.3, 57.8, 52.0, 49.6, 37.4, 34.4,
31.5, 26.8, 19.2, 16.3, 15.3 and 14.6; m/z (CI) 608 (Mþþ18, 7%), 591
(29) and 391 (100).
4.13. (8RS,9SR)-7-[(6-tert-Butyldiphenylsilyloxyhex-2-yn-1-
yloxy)methyl]-8,9-dimethyl-8-hydroxymethyl-1,4-
dioxaspiro[4.5]dec-6-ene 32
Lithium triethylborohydride (1.0 M in tetrahydrofuran,10.59 cm3,
10.59 mmol) was added dropwise to the ester 31 (2.50 g, 4.24 mmol)
in tetrahydrofuran (20 cm3) at 0 ꢁC. After 30 min, the reaction was
poured into ether/water (1:1; 30 cm3). Water (10 cm3) was added
and the aqueous layer was extracted with ether (2ꢂ20 cm3). The
extracts were washed with water (15 cm3), brine (2ꢂ20 cm3), dried
(MgSO4), filtered and concentrated under reduced pressure. Chro-
matography of the residue on silica eluted with ether in light petro-
leum (1:3 to 1:2) gave the title compound 32 (2.17 g, 91%) as
a colourless liquid, Rf¼0.1 (50% ether in light petroleum) (found: Mþ,
562.3119; C34H46O5Si requires M, 562.3114); nmax/cmꢀ1 3434, 3069,
2957, 1664, 1467, 1428, 1107, 1068, 966, 823 and 705; dH 7.70 (4H, m,
Ar–H), 7.44 (6H, m, Ar–H), 5.79 (1H, s, 6-H), 4.22–3.90 (8H, m, 2-H2,
3-H2, 7-CH2 and 10-H2), 3.77 (2H, t, J 6, 60-H2), 3.62 (1H, dd, J 11, 5, 8-
CH), 3.43 (1H, dd, J 11, 10.5, 8-CH0), 2.80 (1H, dd, J 10.5, 4.5, OH), 2.42
(3H, m, 40-H2 and 9-H), 1.80 (4H, m, 10-H2 and 50-H2), 1.09 [9H, s,
SiC(CH3)3], 0.96 (3H, d, J 7, 9-CH3) and 0.78 (3H, s, 8-CH3); dC 143.8,
135.5,133.7, 132.6, 129.5, 127.7, 127.6, 105.2, 87.5, 75.1, 70.4, 64.7, 64.7,
64.4, 62.3, 58.3, 43.2, 37.7, 31.5, 30.1, 26.8,19.2,15.4,15.2 and 14.8; m/z
(CI) 563 (Mþþ1, 100%), 211 (64) and 181 (83); m/z (EI) 562 (Mþ, 8%),
532 (30), 505 (34) and 199 (100).
4.11. (8RS,9SR)-8-(tert-Butyldimethylsilyloxymethyl)-8,9-
dimethyl-7-methylene-6-(1-oxobut-2-ynyl)-1,4-
dioxaspiro[4.5]decane 27
Dimethyl sulfoxide (60 mL, 0.85 mmol) in dichloromethane
(0.25 cm3) was added dropwise at ꢀ78 ꢁC to oxalyl chloride (30
mL,
0.34 mmol) in dichloromethane (1 cm3). After 15 min, the alcohols
26 (a 75:25 mixture of diastereoisomers; 67 mg, 0.17 mmol) in
dichloromethane (0.5 cm3) was added. After a further 3 h, trie-
thylamine (118 mL, 0.85 mmol) was added and the reaction was
warmed to ambient temperature then stirred for 2 h. Water (3 cm3)
was added and the aqueous layer extracted with dichloromethane
(2ꢂ5 cm3). The extracts were washed with water (5 cm3), brine
(5 cm3), dried (MgSO4), filtered and concentrated under reduced
pressure. Chromatography of the residue on silica eluted with ether
in light petroleum (1:3) gave the title compound 27 (43 mg, 65%),
a 70:30 mixture of diastereoisomers, as a pale yellow liquid,
Rf¼0.45 (50% ether in light petroleum) (found: MþþH, 393.2455;
C22H36O4Si requires M, 393.2461); nmax/cmꢀ1 2955, 2218, 1680,
1468, 1254, 1099, 838 and 776; dH 5.20 (0.7H, s, 7-CH), 5.14 (0.3H, s,
7-CH), 5.10 (0.7H, s, 7-CH0), 4.87 (0.3H, d, J 1.5, 7-CH0), 3.86 (4H, m,
2-H2 and 3-H2), 3.57 (3H, m, 8-CH2 and 6-H), 1.98 (1H, m, 9-H), 1.96
(0.9H, s, 40-H3), 1.95 (2.1H, s, 40-H3), 1.61 (2H, m, 10-H2), 0.83 [15H,
m, SiC(CH3)3, 8-CH3 and 9-CH3] and 0.00 [6H, s, Si(CH3)2]; dC 185.8,
147.4,146.4, 115.9,111.3, 109.3, 108.7, 90.0, 80.7, 67.6, 67.0, 65.8, 65.2,
65.0, 64.8, 63.9, 62.1, 44.4, 44.1, 40.6, 38.0, 32.3, 31.5, 25.8, 25.8, 18.2,
17.5, 16.4, 15.8, 4.2, 4.1, ꢀ5.6 and ꢀ5.7; m/z (CI) 393 (Mþ þ1, 100%)
and 168 (17).
4.14. (8RS,9SR)-8-(tert-Butyldimethylsilyloxy)methyl-7-[(6-
tert-butyldiphenylsilyloxyhex-2-yn-1-yloxy)methyl]-8,9-
dimethyl-1,4-dioxaspiro[4.5]dec-6-ene 33
Imidazole (61 mg, 0.89 mmol) followed by tert-butyldime-
thylsilyl chloride (84 mg, 0.556 mmol) was added to the alcohol
33 (250 mg, 0.445 mmol) in dichloromethane (1.5 cm3). After
44 h, aqueous saturated ammonium chloride solution (3 cm3) was
added and the mixture extracted with ether (3ꢂ5 cm3). The ex-
tracts were washed with water (10 cm3), brine (10 cm3), dried
(MgSO4), filtered and concentrated under reduced pressure.
Chromatography of the residue on silica eluted with ether in light
petroleum (1:4) gave the title compound 33 (242 mg, 80%) as
a colourless liquid, Rf¼0.85 (50% ether in light petroleum) (found:
MþþH, 677.4052; C40H61O5Si2 requires M, 677.4057); nmax/cmꢀ1
2954, 1468, 1254, 1104, 1073, 839 and 704; dH 7.64 (4H, m, Ar–H),
7.37 (6H, m, Ar–H), 5.64 (1H, d, J 1, 6-H), 4.15–3.82 (8H, m, 2-H2,
3-H2, 7-CH2 and 10-H2), 3.69 (2H, t, J 6, 60-H2), 3.51 and 3.40 (each
1H, d, J 10.5, 8-CH), 2.34 (2H, tt, J 7.5, 2, 40-H2), 2.22 (1H, m, 9-H),
1.74 (4H, m, 10-H2 and 50-H2), 1.02 [9H, s, SiC(CH3)3], 0.84 [12H, m,
SiC(CH3)3 and 9-CH3], 0.80 (3H, s, 8-CH3) and 0.00 [6H, s, Si(CH3)2];
dC 144.7, 135.5, 133.7, 129.5, 127.6, 124.5, 105.6, 86.3, 76.1, 69.4,
65.2, 64.4, 64.2, 62.4, 57.6, 42.2, 38.0, 31.5, 30.8, 26.8, 25.8, 19.2,
18.1, 15.4, 14.9 and ꢀ5.6; m/z (CI) 677 (Mþþ1, 63%), 391 (62), 341
(31), 168 (100) and 157 (75).
4.12. Methyl (8RS,9SR)-7-[(6-tert-butyldiphenylsilyloxyhex-2-
yn-1-yloxy)methyl]-8,9-dimethyl-1,4-dioxaspiro[4.5]dec-6-
ene-8-carboxylate 31
Alcohol 30 (14.27 g, 40.54 mmol) in tetrahydrofuran (100 cm3)
was added via a cannula to a suspension of sodium hydride (60% in
mineral oil, 1.62 g, 40.54 mmol) in tetrahydrofuran (75 cm3) and
the mixture was heated under reflux for 1 h. After cooling to 0 ꢁC,
a solution of bromide 21 (6.05 g, 18.96 mmol) in tetrahydrofuran
(50 cm3) was added. The mixture was heated under reflux for 5 h,
cooled to ambient temperature and saturated aqueous ammo-
nium chloride (100 cm3) was added. The aqueous layer was
extracted with ether (2ꢂ100 cm3) and the extracts were washed
with water (100 cm3), brine (100 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. Chromatography of the
residue on silica eluted using ether in light petroleum (1:6 to 1:3)
gave the title compound 31 (5.61 g, 50%) as a pale yellow liquid,
Rf¼0.2 (20% ether in light petroleum) (found: MþþH, 591.3136;
C35H47O6Si requires M, 591.3142); nmax/cmꢀ1 2951, 1731, 1667,
1430, 1252, 1143, 1105, 1075 and 705; dH 7.70 (4H, m, Ar–H), 7.44
(6H, m, Ar–H), 5.74 (1H, s, 6-H), 4.07 (6H, m, 2-H2, 3-H2 and 10-H2),
3.95 (2H, m, 7-CH2), 3.76 (2H, t, J 6, 60-H2), 3.70 (3H, s, 8-CO2CH3),
4.15. (8RS,9SR)-8-tert-Butyldimethylsilyloxymethyl-6-(1-
hydroxy-6-tert-butyldiphenylsilyloxyhex-2-yn-1-yl)-8,9-
dimethyl-7-methylene-1,4-dioxaspiro[4.5]decane 34
n-Butyllithium (1.75 M in hexanes, 7.37 cm3, 12.9 mmol) was
added dropwise at ꢀ78 ꢁC to ether 33 (1.74 g, 2.58 mmol) in tetra-
hydrofuran (14 cm3). After 3 h, saturated aqueous ammonium

4208
P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
chloride (25 cm3) was added and the aqueous layer extracted with
ether (3ꢂ25 cm3). The extracts were washed with water (25 cm3),
brine (25 cm3), dried (MgSO4), filtered and concentrated under
reduced pressure. Chromatography of the residue on silica eluted
with ether in light petroleum (1:4) gave the title compounds 34
(1.435 g, 82%), a 67:33 mixture of diastereoisomers, as a colourless
liquid, Rf¼0.8 (50% ether in light petroleum) (found: MþþH,
677.4059; C40H61O5Si2 requires M, 677.4057); nmax/cmꢀ1 3510,
2953,1469,1254,1104, 839 and 704; dH 7.65 (4H, m, Ar–H), 7.37 (6H,
m, Ar–H), 5.74 (0.67H, d, J 1.5, 7-CH), 5.47 (0.33H, s, 7-CH), 5.20
(0.33H, s, 7-CH0), 5.17 (0.67H, s, 7-CH0), 4.95 (0.67H, m, 10-H), 4.87
(0.33H, m, 10-H), 3.97 (4H, m, 2-H2 and 3-H2), 3.72 (0.66H, m, 60-H2),
3.70 (1.34H, t, J 6, 60-H2), 3.48 (3H, m, 8-CH2 and 10-OH), 2.83 (0.67H,
t, J 1.5, 6-H), 2.76 (0.33H, d, J 3.5, 6-H), 2.33 (2H, td, J 7.5, 2, 40-H2),
2.02 (0.67H, m, 9-H), 1.90 (0.33H, m, 9-H), 1.66 (4H, m, 10-H2 and 50-
H2), 1.03 [9H, s, SiC(CH3)3], 0.96 (2.01H, s, 8-CH3), 0.86 [12.99H, m,
SiC(CH3)3, 8-CH3 and 9-CH3], 0.04 [1.98H, s, Si(CH3)2] and 0.00
[4.02H, s, Si(CH3)2]; dC 146.2, 145.0, 135.5, 133.8, 129.5, 127.5, 114.4,
112.8, 112.3, 111.0, 84.7, 84.3, 80.6, 80.2, 69.8, 67.5, 65.8, 64.4, 64.3,
64.0, 63.8, 62.6, 62.5, 61.3, 61.1, 52.3, 51.4, 45.0, 44.0, 39.7, 38.5, 31.9,
31.7, 30.8, 26.8, 25.8, 19.2, 18.7, 18.2, 18.2, 16.8, 16.1, 15.6, 15.6, 15.5,
15.2, ꢀ5.6 and ꢀ5.7; m/z (CI) 694 (Mþþ18, 2%), 677 (3), 582 (11),
565 (10), 368 (33) and 327 (100).
4.17. (4RS,5SR)-2-[(E)-(6-tert-Butyldiphenylsilyloxy-hex-2-
ynylidene)]-4-hydroxymethyl-4,5-dimethyl-3-
methylenecyclohexanone 36
Aqueous hydrogen chloride (10%, 100 mL) was added to the ac-
etals 34 (125 mg, 0.186 mmol) in acetone/water (10:1; 4.4 cm3).
After 15 h, the reaction was diluted with ether (10 cm3) and satu-
rated aqueous sodium bicarbonate (10 cm3) was added. The aque-
ous layer was extracted with ether (2ꢂ10 cm3) and the extracts
were washed with brine (2ꢂ10 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether in light petroleum (1:1) gave the
title compound 36 (43 mg, 46%) as a yellow liquid, Rf¼0.4 (50% ether
in light petroleum) (found: Mþ, 500.2749; C32H40O3Si requires M,
500.2746); nmax/cmꢀ1 3464, 3069, 2956, 2205, 1684, 1611, 1564,
1468, 1427, 1386, 1108, 965, 908, 822, 738 and 704; dH 7.59 (4H, m,
Ar–H), 7.33 (6H, m, Ar–H), 6.44 (1H, t, J 2.5, 10-H), 5.88 and 5.25
(each 1H, s, 3-CH), 3.67 (2H, m, 60-H2), 3.48 (2H, m, 4-CH2), 2.51 (2H,
m, 40-H2), 2.25 (1H, m, 6-H), 2.08 (1H, m, 5-H), 1.73 (1H, m, 6-H0),
1.71 (2H, m, 50-H2), 1.02 (3H, s, 4-CH3), 1.97 [9H, s, SiC(CH3)3] and
0.87 (3H, d, J 7, 5-CH3); dC 135.5, 135.5, 129.6, 129.5, 127.6, 127.5,
117.4, 116.9, 68.8, 62.2, 44.8, 43.4, 31.6, 31.2, 26.8, 19.2, 18.4, 16.8 and
16.1; m/z (CI) 518 (Mþþ18, 100%), 501 (Mþþ1, 98) and 423 (30).
4.16. (8RS,9SR)-8-tert-Butyldimethylsilyloxymethyl-6-(6-tert-
butyldiphenylsilyloxy-1-oxohex-2-yn-1-yl)-8,9-dimethyl-7-
methylene-1,4-dioxaspiro[4.5]decane 35a,b
4.18. (4RS,5SR)-4-tert-Butyldimethylsilyloxymethyl-2-(6-tert-
butyldiphenylsilyloxy-1-oxohex-2-ynyl)-3,4,5-
trimethylcyclohex-2-enone 37
Dimethyl sulfoxide (72
m
L, 1.02 mmol) in dichloromethane
Toluene-4-sulfonic acid (ca. 1 mg) was added to the acetal 35b
(0.25 cm3) was added dropwise to oxalyl chloride (36
mL,
(9 mg, 13 mmol) in acetone (1 cm3) and water (100
mL). After 25 h,
0.408 mmol) in dichloromethane (0.5 cm3) at ꢀ78 ꢁC. After 15 min,
saturated aqueous sodium bicarbonate (1 cm3) was added and the
mixture extracted with ether (3ꢂ2 cm3). The extracts were dried
(MgSO4), filtered and concentrated under reduced pressure. Chro-
matography of the residue on silica eluted with ether in light pe-
troleum (1:3) gave the title compound 37 (4 mg, 44%) as a colourless
liquid, Rf¼0.65 (50% ether in light petroleum) (found: Mþ,
630.3545; C38H54O4Si2 requires M, 630.3560); nmax/cmꢀ1 3070,
2930, 2209, 1675, 1615, 1467, 1254, 1106, 839 and 704; dH 7.64 (4H,
Ar–H), 7.40 (6H, m, Ar–H), 3.70 (2H, t, J 6, 60-H2), 3.66 and 3.56 (each
1H, d, J 10.5, 4-CH), 2.52 (3H, m, 6-H and 40-H2), 2.30 (1H, dd, J 17.5,
12.5, 6-H0), 1.95 (3H, s, 3-CH3), 1.80 (2H, m, 50-H2), 1.04 [9H, s,
SiC(CH3)3], 0.96 (3H, d, J 6.5, 5-CH3), 0.92 (3H, s, 4-CH3), 0.86 [9H, s,
SiC(CH3)3] and 0.04 [6H, s, Si(CH3)2]; dC 195.6, 182.3, 164.4, 140.0,
135.5, 133.6, 129.6, 127.7, 96.4, 81.9, 65.3, 62.2, 44.9, 41.8, 31.9, 30.7,
29.7, 26.8, 25.8, 19.2, 16.3, 16.0, 15.6, 14.7 and ꢀ5.7; m/z (CI) 631
(Mþþ1, 88%), 553 (6), 391 (22), 283 (32), 94 (64) and 58 (100).
the alcohols 34 (138 mg, 0.204 mmol) in dichloromethane (1 cm3)
were added. After 3 h, triethylamine (142 mL,1.02 mmol) was added
and the reaction was allowed to warm to ambient temperature.
After 9 h, water (3 cm3) was added and the aqueous layer extracted
with ether (2ꢂ5 cm3). The extracts were washed with water
(5 cm3), brine (5 cm3), dried (MgSO4), filtered and concentrated
under reduced pressure. Chromatography of the residue on silica
eluted with ether in light petroleum (1:6) gave minor di-
astereoisomer of the title compound 35a (39 mg, 28%) as a colourless
liquid, Rf¼0.35 (20% ether in light petroleum) (found: MþþH,
675.3913; C40H59O5Si2 requires M, 675.3901); nmax/cmꢀ1 2955,
2213, 1682, 1468, 1428, 1254, 1184, 1104, 837 and 704; dH 7.61 (4H,
m, Ar–H), 7.36 (6H, m, Ar–H), 5.13 and 4.87 (each 1H, s, 7-CH), 4.08
(1H, m, 2-H), 3.88 (3H, m, 2-H0 and 3-H2), 3.74 (1H, s, 6-H), 3.68 (2H,
t, J 5.5, 60-H2), 3.65 and 3.55 (each 1H, d, J 10.5, 8-CH), 2.48 (2H, t, J 7,
40-H2), 1.94 (1H, m, 9-H), 1.81–1.43 (4H, m, 10-H2 and 50-H2), 1.00
[9H, s, SiC(CH3)3], 0.88 (3H, s, 8-CH3), 0.83 [12H, m, SiC(CH3)3 and 9-
CH3] and 0.00 [6H, s, Si(CH3)2]; dC 185.7, 147.2, 135.4, 133.5, 129.6,
127.6, 111.4, 109.2, 93.2, 82.5, 66.9, 65.2, 64.9, 62.2, 62.1, 44.1, 40.6,
32.3, 30.7, 26.8, 25.8, 19.2, 18.2, 16.4, 15.7, 15.7 and ꢀ5.6; m/z (CI)
675.5 (Mþþ1, 84%), 327.2 (66), 283.1 (100) and 256.1 (69). The
second fraction corresponded to the major diastereoisomer of the
title compound 35b (58 mg, 42%) as a colourless liquid, Rf¼0.3 (20%
ether in light petroleum) (found: MþþH, 675.3908; C40H59O5Si2
requires M, 675.3901); nmax/cmꢀ1 2955, 2211, 1680, 1468, 1428,
1253, 1104, 836 and 704; dH 7.61 (4H, m, Ar–H), 7.36 (6H, m, Ar–H),
5.19 and 5.07 (each 1H, s, 7-CH), 3.88 (4H, m, 2-H2 and 3-H2), 3.68
(2H, t, J 6, 60-H2), 3.59 and 3.49 (each 1H, d, J 10, 8-CH), 3.49 (1H, br
s, 6-H), 2.47 (2H, t, J 7, 40-H2), 2.02 (2H, m, 10-H and 9-H), 1.75 (2H,
m, 50-H2), 1.56 (1H, m, 10-H0), 1.00 [9H, s, SiC(CH3)3], 0.84 [12H, m,
SiC(CH3)3 and 9-CH3], 0.77 (3H, s, 8-CH3) and 0.00 [6H, s, Si(CH3)2];
dC 185.8, 146.5, 135.4, 133.5, 129.6, 127.7, 116.1, 108.5, 94.0, 81.2, 67.4,
66.3, 65.0, 63.8, 62.1, 44.4, 37.8, 31.5, 30.6, 26.8, 25.8, 19.2, 18.2, 17.4,
15.7, 15.6, ꢀ5.6 and ꢀ5.6; m/z (CI) 675.5 (Mþþ1, 100%), 327.2 (61),
283.2 (38), 168.1 (70) and 88.1 (87).
4.19. (4RS,5SR)-4-tert-Butyldimethylsilyloxymethyl-3-(6-tert-
butyldiphenylsilyloxyhex-2-ynyloxy)methyl-4,5-
dimethylcyclohex-2-enone 38
Pyridinium toluene-4-sulfonate (106 mg, 0.42 mmol) was
added to the acetal 33 (946 mg, 1.40 mmol) in acetone (20 cm3) and
water (0.4 cm3). The reaction was heated under reflux for 3 h, then
cooled to ambient temperature and concentrated under reduced
pressure. The residue was taken up in ether (25 cm3) and washed
with saturated aqueous sodium bicarbonate (10 cm3), water
(10 cm3) and brine (10 cm3), dried (MgSO4), filtered and concen-
trated under reduced pressure to yield the title compound 38
(815 mg, 92%) as a colourless liquid, Rf¼0.75 (50% ether in light
petroleum) (found: MþþH, 633.3782; C38H57O4Si2 requires M,
633.3795); nmax/cmꢀ1 2932, 1671, 1626, 1467, 1255, 1107, 840, 778
and 705; dH 7.62 (4H, m, Ar–H), 7.35 (6H, m, Ar–H), 6.16 (1H, s, 2-H),
4.23 (2H, d, J 1.5, 10-H2), 4.08 (2H, d, J 2, 3-CH2), 3.68 (2H, t, J 6, 60-
H2), 3.55 and 3.50 (each 1H, d, J 11, 4-CH), 2.33 (5H, m, 5-H, 6-H2 and
40-H2), 1.73 (2H, m, 50-H2), 1.01 [9H, s, SiC(CH3)3], 0.90 (6H, m, 8-CH3

P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
4209
and 9-CH3), 0.83 [9H, s, SiC(CH3)3], 0.02 (3H, s, SiCH3) and 0.00 (3H,
s, SiCH3); dC 199.0, 165.2, 135.5, 133.7, 129.5, 127.6, 125.5, 87.0, 75.5,
68.2, 65.2, 62.3, 58.4, 43.2, 41.9, 32.9, 31.5, 26.8, 25.7, 19.2, 18.0, 15.4,
15.3, 15.1 and ꢀ5.7; m/z (CI) 650 (Mþþ18, 9%), 633 (13), 555 (57),
391 (80) and 168 (100).
requires M, 632.3717); nmax/cmꢀ1 3399, 3072, 2931, 1952, 1660,
1471, 1428, 1252, 1098, 1007, 836, 777 and 702; dH 7.56 (4H, m, Ar–
H), 7.32 (6H, m, Ar–H), 6.24 (1H, s, 2-H), 4.82 (3H, m, 10-H and 20-
C]CH2), 3.73 (1H, d, J 10.5, 4-CH), 3.59 (3H, m, 4-CH0 and 50-H2),
3.03 (1H, br s, OH), 2.38 (2H, m, 30-H2), 2.19 (1H, m, 6-H), 1.87 (2H,
m, 5-H and 6-H0), 1.62 (2H, m, 40-H2), 0.97 [9H, s, SiC(CH3)3], 0.87
(3H, d, J 6.5, 5-CH3), 0.85 (3H, s, 4-CH3), 0.80 [9H, s, SiC(CH3)3], 0.01
(3H, s, SiCH3) and 0.00 (3H, s, SiCH3); dC 206.3, 199.7, 135.7, 133.8,
129.8, 128.1, 127.8, 105.2, 77.5, 70.7, 66.6, 62.7, 44.2, 42.0, 33.7, 30.1,
27.1, 25.9, 23.3, 20.4, 19.4, 15.7, 15.5 and ꢀ5.7; m/z (ESþ) 650.4
(Mþþ18, 100%), 633.4 (64), 615.4 (68), 555.3 (39) and 283.2 (5). The
second fraction was the title compound 41b (41 mg, 25%) as a yellow
liquid, Rf¼0.25 (50% ether in light petroleum) (found: Mþ,
632.3723; C38H56O4Si2 requires M, 632.3717); nmax/cmꢀ1 3392,
3052, 2928, 1952, 1662, 1471, 1428, 1389, 1251, 1105, 836, 777 and
703; dH 7.59 (4H, m, Ar–H), 7.35 (6H, m, Ar–H), 6.08 (1H, s, 2-H), 4.91
(2H, m, 20-C]CH2), 4.79 (1H, m,10-H), 3.82 (1H, d, J 10.5, 4-CH), 3.64
(2H, m, 50-H2), 3.54 (1H, d, J 10.5, 4-CH0), 2.44 (2H, m, 30-H2), 2.20
(1H, m, 6-H), 1.88 (2H, m, 5-H and 6-H0), 1.66 (2H, m, 40-H2), 0.99
[9H, s, SiC(CH3)3], 0.90 (3H, d, J 6.5, 5-CH3), 0.84 (3H, s, 4-CH3), 0.82
[9H, s, SiC(CH3)3] and 0.00 [6H, s, Si(CH3)2]; dC 203.1, 198.2, 164.6,
133.9, 132.2, 127.8, 126.3, 125.9, 104.8, 79.0, 70.6, 65.0, 61.6, 42.6,
40.3, 32.2, 28.8, 25.2, 24.1, 22.5, 17.5, 16.5, 15.4, 13.8, ꢀ5.6 and ꢀ5.7;
m/z (ESþ) 650.4 (Mþþ18, 100%), 633.4 (29), 615.3 (57), 555.3 (28)
and 317.2 (4).
4.20. (5RS,6SR)-5-tert-Butyldimethylsilyloxymethyl-4-(6-tert-
butyldiphenylsilyloxyhex-2-ynyloxy)methyl-5,6-dimethyl-2-
triethylsilyloxycyclohexa-1,3-diene 39 and (4RS,5SR)-4-tert-
butyldimethylsilyloxymethyl-3-(6-tert-butyldiphenylsilyl-
oxyhex-2-ynyloxy)methylidene-4,5-dimethyl-1-
triethylsilyloxycyclohexa-1,3-diene 40
The enone 38 (241 mg, 0.381 mmol) in dichloromethane (2 cm3)
was added dropwise to
fluoromethanesulfonate (86
a
solution of triethylsilyl tri-
m
L, 0.381 mmol) and triethylamine
(106 m
L, 0.761 mmol) in dichloromethane (1 cm3) and, after 21 h,
the reaction was diluted with ether (25 cm3). The solution was
washed with saturated aqueous sodium hydrogen carbonate
(10 cm3), water (10 cm3) and brine (10 cm3), dried (MgSO4), filtered
and concentrated under reduced pressure. Chromatography of the
residue on silica eluted with light petroleum containing ether (2%)
and triethylamine (1%) gave the title compound 40 (27 mg, 10%) as
a colourless liquid, Rf¼0.6 (10% ether in light petroleum) (found:
Mþ, 746.4553; C44H70O4Si3 requires M, 746.4582); nmax/cmꢀ1 2955,
1618, 1471, 1426, 1361, 1190, 1105, 1068, 1010, 835, 779 and 701; dH
7.66 (4H, m, Ar–H), 7.37 (6H, m, Ar–H), 5.82 (1H, s, 3-CH), 5.74 (1H,
d, J 1.5, 2-H), 4.30 (2H, t, J 2, 10-H2), 3.73 (2H, t, J 6, 60-H2), 3.58 and
3.17 (each 1H, d, J 9.5, 4-CH), 2.46 (1H, m, 6-H), 2.38 (2H, m, 40-H2),
2.01 (1H, m, 5-H), 1.77 (3H, m, 50-H2 and 6-H0), 1.05 [9H, s,
SiC(CH3)3], 0.97 [12H, m, Si(CH2CH3)3 and 1-CH3], 0.88 [9H, s,
SiC(CH3)3], 0.85 (3H, d, J 7, 6-CH3), 0.69 [6H, q, J 8, Si(CH2CH3)3], 0.01
(3H, s, SiCH3) and 0.00 (3H, s, SiCH3); dC 149.6, 140.4, 135.9, 134.2,
130.0, 128.0, 119.5, 101.8, 87.4, 76.1, 70.3, 62.8, 60.0, 40.9, 35.9, 32.9,
32.0, 27.2, 26.3, 20.2,19.6,18.6,16.3,15.9, 7.1, 5.4, ꢀ5.6 and ꢀ5.7; m/z
(ESþ) 764.6 (Mþþ18, 5%), 747.6 (5) and 164.1 (100). The second
fraction was the title compound 39 (195 mg, 69%) as a colourless
liquid, Rf¼0.55 (10% ether in light petroleum) (found: Mþ,
746.4572; C44H70O4Si3 requires M, 746.4582); nmax/cmꢀ1 3037,
2954, 1471, 1428, 1360, 1248, 1196, 1104, 1006, 969, 836, 778, 739
and 702; dH 7.64 (4H, m, Ar–H), 7.37 (6H, m, Ar–H), 5.73 (1H, d, J 2,
3-H), 4.73 (1H, dd, J 5.5, 2.2, 1-H), 4.06 (2H, t, J 2, 10-H2), 4.03 (2H, s,
4-CH2), 3.72 (2H, t, J 6, 60-H2), 3.49 and 3.43 (each 1H, d, J 9.5, 5-CH),
2.44 (1H, m, 6-H), 2.36 (2H, m, 40-H2),1.75 (2H, m, 50-H2),1.03 [9H, s,
SiC(CH3)3], 0.96 [12H, m, Si(CH2CH3)3 and 5-CH3], 0.86 [12H, m,
SiC(CH3)3 and 6-CH3], 0.64 [6H, q, J 8, Si(CH2CH3)3], 0.00 (3H, s,
SiCH3) and ꢀ0.01 (3H, s, SiCH3); dC 146.5, 140.4, 135.9, 134.2, 130.0,
128.0, 124.6, 109.2, 86.8, 76.6, 67.2, 57.8, 40.6, 33.9, 32.0, 27.2, 26.3,
19.6, 18.7, 16.3, 15.8, 14.5, 7.1, 5.1 and ꢀ5.7; m/z (ESþ) 764.6 (Mþþ18,
8%), 747.6 (17), 316.2 (9) and 162.0 (100).
4.22. (1RS,4RS,5SR)-4-(tert-Butyldimethylsilyloxymethyl)-3-
[(6-tert-butyldiphenylsilyloxyhex-2-ynyloxy)-methyl]-4,5-
dimethylcyclohex-2-en-1-ol 43
Sodium borohydride (0.35 g, 9.15 mmol) was added in portions
to the enone 38 (5.78 g, 9.15 mmol) and cerium(III) chloride hep-
tahydrate (3.41 g, 9.15 mmol) in methanol (50 cm3). After 1 min,
aqueous hydrogen chloride (10%) was added until effervescence
ceased. Water (100 cm3) was then added and the mixture was
extracted with ether (3ꢂ100 cm3). The extracts were washed with
water (100 cm3) and brine (100 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether in light petroleum (1:2) gave the
title compound 43 (5.7 g, 98%) as a colourless liquid, Rf¼0.5 (50%
ether in light petroleum) (found: MþþNH4, 652.4217;
C38H62NO4Si2 requires M, 652.4217); nmax/cmꢀ1 3340, 3071, 2930,
1468, 1254, 1106, 843, 776 and 704; dH 7.65 (4H, m, Ar–H), 7.38 (6H,
m, Ar–H), 5.77 (1H, s, 2-H), 4.22 (1H, m, 1-H), 4.11 (1H, dt, J 13, 1.5,
3-CH), 4.08 (2H, m, 10-H2), 3.96 (1H, dt, J 13, 1.5, 3-CH0), 3.71 (2H, t, J
6, 60-H2), 3.49 and 3.38 (each 1H, d, J 10, 4-CH), 2.36 (2H, tt, J 7, 2, 40-
H2), 2.01 (1H, m, 5-H), 1.82 (1H, m, 6-H), 1.75 (2H, pent, J 7, 50-H2),
1.41 (1H, m, 6-H0), 1.03 [9H, s, SiC(CH3)3], 0.83 [15H, m, Si(CH3)3, 4-
CH3 and 5-CH3] and 0.00 [6H, s, Si(CH3)2]; dC 141.2, 135.5, 133.7,
130.0, 129.5, 127.6, 86.3, 76.2, 69.8, 67.6, 64.8, 62.4, 57.6, 42.2, 36.8,
31.5, 30.6, 26.8, 25.7, 19.2, 18.1, 16.1, 15.5, 15.3, ꢀ5.6 and ꢀ5.7; m/z
(CI) 652 (Mþþ18, 9%), 617 (38), 485 (32), 335 (89) and 704 (100).
4.21. (4RS,5SR)-4-tert-Butyldimethylsilyloxymethyl-3-(5-tert-
butyldiphenylsilyloxy-1-hydroxy-2-vinylidene-pent-1-yl)-4,5-
dimethylcyclohex-2-enones 41a, b
4.23. (1RS,4RS,5SR)-4-(tert-Butyldimethylsilyloxymethyl)-3-
[(6-tert-butyldiphenylsilyloxyhex-2-ynyloxy)-methyl]-4,5-
dimethyl-1-tri-isopropylsilyloxycyclohex-2-ene 44
n-Butyllithium (1.6 M in hexanes, 0.81 cm3, 1.30 mmol) was
added dropwise to the enol ether 39 (194 mg, 0.26 mmol) in tet-
rahydrofuran (2.5 cm3) at ꢀ78 ꢁC. After 2 h, aqueous hydrochloric
acid (1 N; 3 cm3) was added and the mixture was allowed to warm
to ambient temperature. After stirring for 1 h, the mixture was
diluted with water (10 cm3) and extracted with ether (3ꢂ10 cm3).
The extracts were washed with brine (10 cm3), dried (MgSO4), fil-
tered and concentrated under reduced pressure. Chromatography
of the residue on silica eluted with ether in light petroleum (1:2)
gave the title compound 41a (41 mg, 25%) as a yellow liquid, Rf 0.45
(50% ether in light petroleum) (found: Mþ, 632.3678; C38H56O4Si2
Tri-isopropylsilyl chloride (0.42 cm3, 1.98 mmol) was added to
the alcohol 43 (1.254 g, 1.98 mmol) and imidazole (0.27 g,
3.96 mmol) in dichloromethane (5 cm3). After 46 h at ambient
temperature, water (15 cm3) was added and the mixture was
extracted with ether (3ꢂ30 cm3). The extracts were washed with
water (30 cm3) and brine (30 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. Chromatography of the
residue on silica eluted with ether in light petroleum (1:20) gave
the title compound 44 (1.552 g, 99%) as a colourless oil, Rf¼0.95 (10%

4210
P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
ether in light petroleum) (found: MþþNH4, 808.5540;
C47H82NO4Si3 requires M, 808.5551); nmax/cmꢀ1 2934, 1465, 1253,
1103,1067, 840, 776 and 703; dH 7.66 (4H, m, Ar–H), 7.40 (6H, m, Ar–
H), 5.75 (1H, s, 2-H), 4.32 (1H, m, 1-H), 4.11 (1H, d, J 13, 3-CH), 4.07
(2H, m, 10-H2), 3.98 (1H, d, J 13, 3-CH0), 3.72 (2H, t, J 6, 60-H2), 3.50
and 3.40 (each 1H, d, J 11, 4-CH), 2.36 (2H, m, 40-H2), 1.98 (1H, m, 5-
H), 1.76 (3H, m, 50-H2 and 6-H), 1.52 (1H, m, 6-H0), 1.07 [30H, m,
Si(CH(CH3)2)3 and SiC(CH3)3], 0.85 [15H, m, SiC(CH3)3, 5-CH3 and 4-
CH3] and 0.00 [6H, s, Si(CH3)2]; dC 139.2, 135.5, 133.8, 132.2, 129.5,
127.5, 86.1, 70.1, 68.1, 65.0, 62.4, 57.0, 42.2, 37.2, 31.6, 30.7, 26.8, 25.8,
19.2, 18.1, 16.1, 15.7, 15.3, 12.3, ꢀ5.6 and ꢀ5.7; m/z (CI) 808 (Mþþ18,
52%), 791 (6), 617 (48), 455 (61), 439 (72), 281 (96) and 135 (100).
4.25. (2RS,3RS,5SR,6RS)-6-(tert-Butyldimethylsilyloxy-
methyl)-2-(6-tert-butyldiphenylsilyloxy-1-oxohex-2-ynyl)-
5,6-dimethyl-3-(tri-isopropylsilyloxy)-1-methyl-
enecyclohexane 47
Tetra-n-propylammonium perruthenate (9 mg, 0.025 mmol)
was added to a stirred suspension of alcohol 45a (202 mg,
0.25 mmol), N-methylmorpholine N-oxide (59 mg, 0.501 mmol)
and crushed 4 Å molecular sieves in dichloromethane (2 cm3). After
70 h, the reaction was diluted with dichloromethane (20 cm3). The
organic layer was washed with saturated aqueous sodium thio-
sulfate (10 cm3), brine (10 cm3) and saturated aqueous copper(II)
sulfate (10 cm3), dried (MgSO4), filtered and concentrated under
reduced pressure. Chromatography of the residue on silica eluted
with ether in light petroleum (1:19) gave the title compound 47
(156 mg, 77%) as a colourless oil, Rf¼0.75 (10% ether in light pe-
troleum) (found: MþþH, 789.5135; C47H77O4Si3 requires M,
789.5129); nmax/cmꢀ1 3071, 2951, 2214, 1675, 1466, 1252, 1106, 840,
776 and 703; dH 7.61 (4H, m, Ar–H), 7.36 (6H, m, Ar–H), 4.99 and
4.68 (each 1H, d, J 1, 1-CH), 4.15 (1H, td, J 10.5, 4.5, 3-H), 3.67 (2H, t, J
6, 60-H2), 3.64 and 3.46 (each 1H, d, J 10.5, 6-CH), 3.37 (1H, d, J 10, 2-
H), 2.46 (2H, t, J 6.5, 40-H2), 1.76 (4H, m, 50-H2, 4-H and 5-H), 1.46
(1H, m, 4-H0), 1.01 [30H, m, Si(CH(CH3)2)3 and SiC(CH3)3], 0.82 [15H,
m, SiC(CH3)3 5-CH3 and 6-CH3] and 0.00 [6H, s, Si(CH3)2]; dC 189.2,
148.0, 135.4,133.6,129.6, 127.6, 110.1, 93.7, 82.0, 71.9, 66.1, 64.1, 62.2,
44.1, 39.4, 31.9, 30.8, 26.8, 25.8, 19.2, 18.2, 16.4, 15.9, 15.7, 12.7 and
ꢀ5.7; m/z (CI) 790 (24%), 616 (4), 440 (6), 168 (71), 135 (72) and 58
(100).
4.24. (2RS,3RS,5SR,6RS)- and (2SR,3RS,5SR,6RS)-6-(tert-
Butyldimethylsilyloxymethyl)-2-(1-hydroxy-6-tert-
butyldiphenylsilyloxyhex-2-ynyl)-5,6-dimethyl-3-(tri-
isopropylsilyloxy)-1-methylenecyclohexanes 45a,b and 46
n-Butyllithium (1.6 M in hexanes, 6.13 cm3, 9.81 mmol) was
added dropwise at ꢀ78 ꢁC to the ether 44 (1.552 g, 1.96 mmol) in
tetrahydrofuran (20 cm3). After 4 h, water (10 cm3) was added and
the aqueous layer was extracted with ether (2ꢂ15 cm3). The ex-
tracts were washed with water (20 cm3) and brine (20 cm3), dried
(MgSO4), filtered and concentrated under reduced pressure. Chro-
matography of the residue on silica eluted with ether in light pe-
troleum (1:30 to 1:10) gave the title compound 45a (450 mg, 29%) as
a colourless liquid, Rf¼0.65 (10% ether in light petroleum) (found:
MþþNH4, 808.5527; C47H82NO4Si3 requires M, 808.5551); nmax
/
cmꢀ1 3497, 3050, 2932, 1636, 1467, 1428, 1253, 1108, 1035, 838, 776
and 704; dH 7.62 (4H, m, Ar–H), 7.36 (6H, m, Ar–H), 4.98 and 4.89
(each 1H, s, 1-CH), 4.52 (1H, dd, J 9, 3, 10-H), 4.36 (1H, d, J 9.5, OH),
4.09 (1H, td, J 9.5, 5, 3-H), 3.66 (2H, t, J 6, 60-H2), 3.57 and 3.49 (each
1H, d, J 10.5, 6-CH), 2.55 (1H, dd, J 9, 3, 2-H), 2.30 (2H, m, 40-H2), 1.81
(1H, m, 5-H), 1.76–1.50 (4H, m, 4-H2 and 50-H2), 1.08 [21H, m,
Si(CH(CH3)2)3], 1.01 [9H, s, SiC(CH3)3], 0.82 [15H, m, SiC(CH3)3, 5-
CH3 and 6-CH3] and 0.00 [6H, s, Si(CH3)2]; dC 148.6, 135.5, 133.8,
129.5, 127.5, 110.1, 86.2, 80.2, 74.7, 66.9, 64.5, 62.6, 52.8, 44.1, 39.8,
32.3, 31.7, 26.8, 25.8, 19.2, 18.2, 17.1, 16.0, 15.6, 13.1, ꢀ5.7 and ꢀ5.7;
m/z (CI) 792 (6%), 618 (23), 439 (29), 368 (64) and 135 (100). The
second fraction was the title compound 46 (322 mg, 21%), a colour-
less liquid, Rf¼0.6 (10% ether in light petroleum) (found: MþþNH4,
808.5561; C47H82NO4Si3 requires M, 808.5551); nmax/cmꢀ1 3582,
3472, 3050, 2935, 1640, 1466, 1428, 1388, 1253, 1103, 838, 776 and
703; dH 7.65 (4H, m, Ar–H), 7.37 (6H, m, Ar–H), 5.15 and 5.06 (each
1H, s, 1-CH), 4.76 (1H, m, 10-H), 4.44 (1H, m, 3-H), 3.69 (2H, t, J 6, 60-
H2), 3.43 (2H, s, 6-CH2), 2.63 (1H, dd, J 8.5, 4.5, 2-H), 2.34 (2H, m, 40-
H2), 1.90–1.69 (4H, m, 5-H, 4-H and 50-H2), 1.43 (1H, m, 4-H0), 1.05
[21H, m, Si(CH(CH3)2)3], 1.03 [9H, s, SiC(CH3)3], 0.93 (3H, s, 6-CH3),
0.86 [12H, m, SiC(CH3)3 and 5-CH3] and 0.00 [6H, s, Si(CH3)2]; dC
148.5, 135.5, 133.8, 129.5, 127.5, 111.3, 85.9, 80.2, 71.2, 69.7, 62.7,
62.6, 52.4, 44.9, 38.5, 31.7, 30.9, 26.8, 25.9, 19.2, 18.2, 18.2, 16.8, 16.7,
15.6, 12.9, ꢀ5.6 and ꢀ5.6; m/z (CI) 809 (2%), 774 (19), 600 (18), 439
(42), 368 (94) and 135 (100). The third fraction was the title com-
pound 45b (288 mg, 19%), a pale yellow liquid, Rf¼0.4 (10% ether in
light petroleum) (found: MþþNH4, 808.5539; C47H82NO4Si3 re-
quires M, 808.5551); nmax/cmꢀ1 3457, 3071, 2954, 1636, 1466, 1253,
1105, 1066, 838 and 703; dH 7.62 (4H, m, Ar–H), 7.35 (6H, m, Ar–H),
5.19 and 5.09 (each 1H, s, 1-CH), 4.86 (1H, td, J 6.5, 2, 10-H), 3.69 (3H,
m, 3-H and 60-H2), 3.62 and 3.48 (each 1H, d, J 10.5, 6-CH), 2.54 (1H,
dd, J 10, 6.5, 2-H), 2.29 (2H, td, J 7.5, 1.5, 40-H2), 1.82–1.42 (5H, m, 5-
H, 4-H2 and 50-H2), 1.05 [21H, m, Si(CH(CH3)2)3], 1.00 [9H, s,
SiC(CH3)3], 0.83 [9H, s, SiC(CH3)3], 0.80 (6H, m, 5-CH3 and 6-CH3)
and 0.00 [6H, s, Si(CH3)2]; dC 148.5, 135.5, 133.8, 129.5, 127.5, 109.6,
86.5, 80.1, 75.6, 67.0, 63.5, 62.6, 52.9, 44.4, 40.9, 32.9, 31.7, 26.8, 25.7,
19.2, 18.2, 18.1, 16.3, 15.8, 15.5, 12.9 and ꢀ5.7; m/z (CI) 809 (3%), 792
(6), 618 (66), 368 (81) and 135 (100).
4.26. (2SR,3RS,5SR,6RS)-6-(tert-Butyldimethylsilyloxy-
methyl)-2-(6-tert-butyldiphenylsilyloxy-1-oxohex-2-ynyl)-
5,6-dimethyl-3-(tri-isopropylsilyloxy)-1-methyl-
enecyclohexane 48
Dimethyl sulfoxide (60 mL, 0.85 mmol) in dichloromethane
(0.25 cm3) was added at ꢀ78 ꢁC to a solution of oxalyl chloride
(30 m
L, 0.34 mmol) in dichloromethane (0.5 cm3). After 15 min, the
alcohol 46 (54 mg, 0.068 mmol) in dichloromethane (1 cm3) was
added. After stirring at ꢀ78 ꢁC for 7 h, triethylamine (118
mL,
0.850 mmol) was added. After a further 14 h, water (3 cm3) was
added and the mixture extracted with ether (3ꢂ5 cm3). The ex-
tracts were washed with water (5 cm3), brine (5 cm3), dried
(MgSO4), filtered and concentrated under reduced pressure. Chro-
matography of the residue on silica eluted with ether in light pe-
troleum (1:19) gave the title compound 48 (43 mg, 81%) as
a colourless oil, Rf¼0.7 (10% ether in light petroleum) (found:
MþþH, 789.5113; C47H77O4Si3 requires M, 789.5129); nmax/cmꢀ1
3071, 2952, 2209, 1682, 1623, 1465, 1253, 1107, 837, 776 and 703; dH
7.61 (4H, m, Ar–H), 7.35 (6H, m, Ar–H), 5.08 (2H, m, 1-CH2), 3.82
(1H, dt, J 12, 6, 3-H), 3.69 (2H, t, J 6, 60-H2), 3.65 (1H, d, J 6, 2-H), 3.59
and 3.40 (each 1H, d, J 10.5, 6-CH), 2.46 (2H, t, J 7.5, 40-H2), 2.32 (1H,
m, 4-H),1.75 (3H, m, 50-H2 and 5-H), 1.58 (1H, m, 4-H0), 1.01 [30H, m,
Si(CH(CH3)2)3 and SiC(CH3)3], 0.83 [12H, m, SiC(CH3)3 and 5-CH3],
0.73 (3H, s, 6-CH3) and 0.00 [6H, s, Si(CH3)2]; dC 186.4, 147.3, 135.4,
133.6, 129.6, 127.6, 116.0, 92.5, 81.9, 71.6, 66.3, 65.2, 62.2, 44.1, 36.5,
31.9, 30.7, 26.8, 25.8, 19.2, 18.2, 18.1, 18.0, 17.6, 15.7, 15.5, 12.3 and
ꢀ5.6; m/z (CI) 790 (19%), 616 (6), 538 (5), 439 (5), 168 (53) and 135
(100).
4.27. Crystal data for methyl (1RS,6SR)-1,2,6-trimethyl-4-
oxocyclohex-2-ene-1-carboxylate 20
C11H16O3, MW 196.24, triclinic, space group Pꢀ1, a¼8.170(1),
b¼11.691(2), c¼6.381(2) Å,
a
¼91.35(2),
b
¼109.51(2),
(Cu
g
¼107.39(1)ꢁ,
V¼543.0(2) Å3, Z¼2, Dc¼1.200 g cmꢀ3
,
m
K
a
)¼0.704 mmꢀ1
,
F(000)¼212, T¼296 K. Crystal dimensions were 0.4ꢂ0.4ꢂ0.35 mm;

P.D.P. Shapland, E.J. Thomas / Tetrahedron 65 (2009) 4201–4211
14. Mori, S.; Nakamura, E. Chem.dEur. J. 1999, 5, 1534.
4211
2379 reflections measured, 2225 independent reflections
15. On the basis of steric interactions between the alkynyl group and the acetal in
the transition state for the [2,3]-Wittig rearrangements, it is suggested that the
two products were diastereoisomers 26a and 26b. This is consistent with the
formation of two diastereomeric products from the rearrangement of acetal 33
and the formation of three products from the rearrangement of the protected
(Rint¼0.042), R1¼0.057 for the 1717 reflections with I>2
s(I),
wR(F2)¼0.1817 (all data). CCDC 714071. X-ray data have been de-
posited with the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK; fax (þ44) 122 333 6033.
alcohol 44. Moreover, the major product isolated from
a [2,3]-Wittig re-
arrangement of an analogous albeit slightly more complex system en route to
the phomactin nucleus was shown to have the relative configuration at C(2)
and C(10) as shown here for products 26a and 26b (see Ref. 16).
Acknowledgements
We thank GlaxoSmithKline for support through the CASE
scheme (to P.D.P.S.) and Dr. M. Helliwell for the X-ray crystal
structure.
OH
OH
Me
H
Me
H
1'
O
1'
O
TBSO
Me
TBSO
Me
2
2
Me
Me
O
O
Supplementary data
26a
26b
Supplementary data with full experimental procedures for the
synthesis of intermediates 28–30 and 49, 50, 53–65, can be found in
the online version. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.03.031.
16. Balnaves, A. S.; McGowan, G.; Shapland, P. D. P.; Thomas, E. J. Tetrahedron Lett.
2003, 44, 2713.
17. Following the provisional stereochemical assignments to products 26, it is
suggested that the two products from the rearrangement of ether 33 had the
relative stereochemistry at C(2) and C(10) as shown for 34a and 34b, oxidation
giving the corresponding ketones 35a and 35b. An NOE observed for H(6) on
irradiation of 8-CH3 for the minor ketone 35a suggested that this had the
structure shown below. The major rearrangement product was therefore pro-
visionally assigned as alcohol 34b. This assignment was not confirmed in this
series but is consistent with results obtained later for analogous systems (see
Ref. 18).
References and notes
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N. I. Tetrahedron 2000, 56, 10185; (e) Seth, P. P.; Totah, N. I. Org. Lett. 2000, 2,
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3, 1491; (j) Houghton, T. J.; Choi, S.; Rawal, V. H. Org. Lett. 2001, 3, 3615; (k)
Mohr, P. J.; Halcomb, R. L. Org. Lett. 2002, 4, 2413; (l) Cheing, J. W. C.; Goldring,
W. P. D.; Pattenden, G. Chem. Commun. 2003, 2788; (m) Foote, K. M.; Hayes, C. J.;
John, M. P.; Pattenden, G. Org. Biomol. Chem. 2003, 1, 3917; (n) Cole, K. P.; Hsung,
R. P. Org. Lett. 2003, 5, 4843; (o) Cole, K. P.; Hsung, R. P. Chem. Commun. 2005,
5784; (p) Ryu, K.; Cho, Y.-S.; Jung, S.-I.; Cho, C.-G. Org. Lett. 2006, 8, 3343; (q)
Teng, D.; Wang, B.; Augatis, A. J.; Totah, N. I. Tetrahedron Lett. 2007, 48, 4605; (r)
Huang, J.; Wang, H.; Wu, C.; Wulff, W. D. Org. Lett. 2007, 9, 2799; (s) Kallan, N.
C.; Halcomb, R. L. Org. Lett. 2000, 2, 2687; (t) Goldring, W. P. D.; Alexander, S. P.
H.; Kendall, D. A.; Pattenden, G. Bioorg. Med. Chem. Lett. 2005, 15, 3263.
8. Goldring, W. P. D.; Pattenden, G. Acc. Chem. Res. 2006, 39, 354.
OH
O
OH
O
Me
H
Me
H
TBSO
Me
TBSO
Me
+
O
O
TBDPSO
TBDPSO
34a
34b
nOe
Me
O
O
O
O
H
O
Me
H
O
TBSO
Me
TBSO
Me
8
6
35a
35b
TBDPSO
TBDPSO
18. Blackburn, T. J.; Helliwell, M.; Kilner, M. J.; Lee, A. T. L.; Thomas, E. J. Tetrahedron
Lett., in press.
19. Following the discussion above, the major and minor isomers of product 45 are
believed to be epimers 45a and 45b, respectively, and the C(2)-epimer is as-
signed the structure 46, the configuration at C(2) in these compounds being
unambiguously established by J2,3
.
OH
OH
Me
H
Me
H
TBSO
Me
TBSO
Me
2
3
2
3
OTIPS
OTIPS
9. (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885; (b) Nakai, T.; Mikami, K.
Synthesis 1991, 594; (c) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105.
10. Marsden, A.; Thomas, E. J. Arkivoc 2002, ix, 78.
H
H
45a
TBDPSO
45b
TBDPSO
11. (a) Acheson, R. M.; Flowerday, R. F. J. Chem. Soc., Perkin Trans. 1 1974, 2339; (b)
Linker, T.; Frohlich, L. J. Am. Chem. Soc. 1995, 117, 2694.
12. (a) Shultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824; (b) Shultz, A. G.;
Taveras, A. G.; Harrington, R. E. Tetrahedron Lett. 1988, 29, 3907.
OH
Me
H
TBSO
2
3
13. (a) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J. Org. Chem.
1988, 53, 2087; (b) Murray, R. W.; Shiang, D. L. J. Chem. Soc., Perkin Trans. 2 1990,
349; (c) Troisi, L.; Cassidei, L.; Lopez, L.; Mello, R.; Curci, R. Tetrahedron Lett.
1989, 30, 257.
Me
OTIPS
H
46
TBDPSO