A formal synthesis of (+)-pyripyropene A using a biomimetic epoxy-olefin cyclisation: Effect of epoxy alcohol/ether on cyclisation efficiency

Article abstract of DOI:10.1039/a906589j

The synthesis of the decalin sub-unit 2 of (+)-pyripyropene A 1 (a key intermediate in the first total synthesis) is described. The key step involves a biomimetic epoxy-olefin cyclisation using an allylsilane as the terminating group. Whilst attempts to cyclise epoxy alcohol 6 were unfruitful, cyclisation of the protected epoxy benzyl ether 7 using BF₃·OEt₂ was successful, yielding bicyclic ester 25. Isomerisation of the exocyclic double bond into conjugation with the ester group proved to be problematic, although successful conditions were ultimately found. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a906589j

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A formal synthesis of (؉)-pyripyropene A using a biomimetic
epoxy-olefin cyclisation: effect of epoxy alcohol/ether on
cyclisation efficiency
Varinder K. Aggarwal,*a Paul A. Bethela and Robert Gilesb
a Department of Chemistry, University of Sheffield, Sheffield, UK S3 7HF
b SmithKline Beecham, Old Powder Mills, Tonbridge, Kent, UK TN11 9AN
Received (in Cambridge) 13th August 1999, Accepted 10th September 1999
The synthesis of the decalin sub-unit 2 of (ϩ)-pyripyropene A 1 (a key intermediate in the first total synthesis) is
described. The key step involves a biomimetic epoxy-olefin cyclisation using an allylsilane as the terminating group.
Whilst attempts to cyclise epoxy alcohol 6 were unfruitful, cyclisation of the protected epoxy benzyl ether 7 using
BF3ؒOEt2 was successful, yielding bicyclic ester 25. Isomerisation of the exocyclic double bond into conjugation
with the ester group proved to be problematic, although successful conditions were ultimately found.
Introduction
1
˜
Pyripyropenes A–L, isolated by Omura and co-workers from
a fermentation broth of Aspergillus fumigatus, are the most
effective naturally occurring inhibitors of acyl-CoA:cholesterol
acyltransferase (ACAT), the enzyme responsible for intra-
cellular esterification of cholesterol. Inhibition of the ACAT
enzyme represents a new approach to the prevention and
treatment of atherosclerosis and hypercholesterolemia2 since
evidence suggests that ACAT inhibitors may lower plasma
cholesterol levels and prevent the accumulation of cholesteryl
esters in arterial lesions.
The simplest member of the family, pyripyropene E 4,
was biomimetically constructed in a racemic form by Parker
and Resnick3 and, later, in an enantiomerically pure form by
4
˜
Omura and Smith and co-workers. Both approaches utilised
an epoxide initiated polyene cyclisation5 to deliver the pyri-
pyropene skeleton, the latter using the cyclisation of substrate
5. The most active member of the family, (ϩ)-pyripyropene A
˜
1, was synthesised by Omura and Smith from the (ϩ)-Wieland–
Miescher ketone 3 in 19 steps (Scheme 1).4 Although a bio-
mimetic polyene cyclisation has been used to prepare pyri-
pyropene E 4, it was surprising that this strategy had not
been adopted for pyripyropene A 1 as the required epoxide
contains a neighbouring alcohol group and as such could be
easily obtained in enantiomerically pure form by Sharpless
epoxidation.6
We envisioned a short biomimetic route to the decalin sub-
˜
unit 2, a key intermediate in the Omura–Smith synthesis
(prepared in 10 steps from 3), utilising the cyclisation of
epoxy-allylsilanes of type 6 or 7 (Scheme 2).7 Previously,
Weiler had shown that allylsilanes bearing esters were suffi-
ciently nucleophilic to undergo epoxy-olefin cyclisation in
good yield.8 The advantages of such a sequence are rapid con-
struction of the carbocyclic ring system and excellent stereo-
chemical control at the four stereocentres present in the target
decalin 2.
Scheme 1
Results and discussion
First generation synthesis
Scheme 2
Initially, the synthesis and cyclisation of epoxy-allylsilane 6
was attempted. The cyclisation substrate, epoxy alcohol 6,
was synthesised in 5 steps from geranyl bromide 8 (Scheme 3).
Initial alkylation of geranyl bromide 8 with the dianion of
methyl acetoacetate9 afforded the β-keto ester 9 and subsequent
reaction with NaH and (EtO)2POCl gave the known enol
phosphate 10 in good yield.10 Regioselective hydroxylation11
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321
This journal is © The Royal Society of Chemistry 1999
3315

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SnCl4 yielded bicyclic ethers 15 and 16 along with chlorohydrin
13. We were disappointed at the poor results as there are known
literature examples of (epoxy alcohol)-olefin cyclisations,14
however, in each of these cases only a monocyclic product was
sought.
We therefore decided to protect the free hydroxy group as a
benzyl ether as Tanis et al. have demonstrated in the cyclisation
of such a benzyl ether, with furan as the terminating group,
in the synthesis of (ϩ)-aphidicolin.15 In a comparison of pro-
tecting groups, Tanis found that a benzyl ether gave higher
yields than a TBDMS ether in the epoxy–olefin cyclisation
reaction and so we elected to make the benzyl ether 7. How-
ever when substrate 6 was subjected to standard benzylation
conditions (NaH, BnBr) none of the desired product was
obtained; silyl ether 17 and benzyl ether 18 were obtained
instead (Scheme 5). Clearly the allylsilane bearing the ester
Scheme 3 Reagents and conditions: i, methyl acetoacetate, NaH,
nBuLi, THF, 0 ЊC, then 8, 75%; ii, NaH, (EtO)2POCl, Et2O, 86%;
iii, TBHP, SeO2 (cat.), salicylic acid, DCM, 44%; iv, TMSCH2MgCl,
Ni(acac)2 (cat.), Et2O, 50%; v, TBHP, (ϩ)-DET, Ti(OiPr)4, DCM, 70%,
90% ee.
using SeO2 gave the trans-allylic alcohol 11, which was subjected
to a nickel catalysed cross coupling reaction8,12 with TMSCH2-
MgCl to form allylsilane 12. Subsequent Sharpless epoxid-
ation6 gave rise to the cyclisation substrate, epoxy alcohol 6, in
70% yield and 90% ee. Unfortunately, all attempts to cyclise
the unprotected epoxy alcohol 6 failed. For example, using
BF3ؒOEt2 only mixtures of unidentifiable acyclic and mono-
cyclic products were obtained and the use of MeAlCl2 (Corey’s
preferred cyclisation catalyst)5b–d,13 resulted in the formation of
chlorohydrins 13 and 14 as shown in Scheme 4. The use of
Scheme 5 Reagents and conditions: i, NaH, BnBr, THF; ii, PhCHN2,
HBF4 (cat.), CH2Cl2, Ϫ40 ЊC, 66% yield (7:19, 2:1).
moiety was sensitive to the basic conditions employed. The use
of mildly acidic conditions was tested (PhCHN2, HBF4 (cat.))16
and resulted in formation of the required benzyl ether 7
together with the inseparable rearrangement product 19 arising
from acid catalysed epoxide ring opening. Treatment of this
mixture of products with BF3ؒOEt2 did provide decalin 25,
but in rather poor yield. Due to the difficulties experienced in
the benzylation step it was decided to introduce the benzyl
group at an earlier stage in the synthesis.
Second generation synthesis
The known allylic alcohol 20, derived from geraniol in 5 steps,15
was converted to bromide 21 upon treatment with MsCl–Et3N
followed by LiBr at Ϫ78 ЊC (Scheme 6). Low temperature and a
controlled amount of LiBr were required to minimise opening
of the epoxide ring whilst ensuring displacement of any allylic
chloride present. Initially, the allylic alcohol 20 was treated with
MsCl–Et3N at Ϫ40 ЊC followed by 3 equivalents of LiBr at
room temperature for 30 min.17 These conditions resulted in the
formation of the required allylic bromide 21 in 65% yield and a
10% yield of the inseparable allylic chloride.18 A third product
was identified as the bromohydrin resulting from bromide
addition to the epoxide ring.19 The use of 10 equivalents of
LiBr for 30 min reduced the amount of allylic chloride (3%)
but, as expected, led to an increase in bromohydrin formation
(13%). In an attempt to reduce these side products, the reaction
was carried out at Ϫ78 ЊC throughout both the mesylation
and bromination steps. Optimum conditions (i, MsCl–Et3N,
Scheme 4 Reagents and conditions: i, MeAlCl2, CH2Cl2, room temp.;
ii, SnCl4, CH2Cl2, room temp.
3316
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321

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Table 1 Variation of alkene isomerisation with time
Time/ha
Yield of 2 (%)
Yield of 28 (%)
0.5
1
2
3
4
14
32
45
47
51
34
42
15
19
21
a Time of reflux of substrate 25 with NaH prior to addition of BnBr.
Fig. 1
Initial attempts to isomerise the exocyclic double bond of
alcohol 25 with DBU–MeOH or KOtBu–tBuOH failed, with
starting material being recovered. Treatment with KH–THF
t
followed by a BuOH quench resulted in isomerisation to the
trisubstituted alkene 26 instead (Fig. 1). Fortuitously, benzyl-
ation of alcohol 25 by reaction with excess NaH in refluxing
THF prior to the addition of BnBr resulted in partial iso-
merisation to the conjugated alkene 2. Increasing the time
of reflux with NaH to 4 hours led to a 51% yield of alkene
2 (Table 1). Evidently the diene enolate is quenched by a
proton at the γ position, but if the protonation regenerates
a base, the tetrasubstituted alkene isomerises to the thermo-
dynamically more stable trisubstituted alkene.21 Decalin 2 was
spectroscopically identical22 to the data reported by Omura
˜
and Smith.4
The remaining unchanged exocyclic double bond isomer
28,23 recovered in 21% yield, was subjected to a range of iso-
merisation conditions. Refluxing the substrate in EtOH in
Scheme 6 Reagents and conditions: i, MsCl, Et3N, THF, Ϫ78 ЊC, 1 h,
then LiBr (3 equiv.), acetone, Ϫ78 ЊC, 40 min, 79%; ii, methyl aceto-
acetate, NaH, BuLi, THF, 0 ЊC, then 21, 78%; iii, BF3ؒOEt2, CH2Cl2,
61%; iv, NaH, (EtO)2POCl, Et2O, 93%; v, TMSCH2MgCl, Ni(acac)2
(cat.), Et2O, 0 ЊC, 54%; vi, BF3ؒOEt2, CH2Cl2, 54%; vii, NaH, BnBr,
THF, reflux, 51%.
n
24
the presence of RhCl3 again resulted in the formation of the
trisubstituted isomer, alkene 27. Frejd et al. reported similar
isomerisation problems in a related system during the synthesis
of a Taxol A-ring building block.14a It was reported that the
considerable isomerisation difficulties encountered were over-
come by heating the exocyclic double bond isomer to 185 ЊC
in neat DBU for 1 hour resulting in 58% conversion. Similar
conditions (150 ЊC, neat DBU) were used with alkene 27 but
only partial isomerisation occurred after 1 hour and prolonged
heating resulted in decomposition of the substrate.
Ϫ78 ЊC, 1 h; ii, 3 equivalents LiBr, Ϫ78 ЊC, 40 min) resulted
in formation of the desired allylic bromide 21 in 79% yield
along with 7% of the allylic chloride. A small amount of
bromohydrin was removed by chromatography. The relatively
unstable bromide 21 was then employed in the alkylation step
with the dianion of methyl acetoacetate9 to afford β-keto ester
22 in 78% yield. Treatment of this compound with BF3ؒOEt2
resulted in cyclisation, but, as expected, through oxygen rather
than carbon to furnish the oxabicycle 23.20 Conversion of β-
keto ester 22 to enol phosphate 24 [NaH, (EtO)2POCl, Et2O]10
followed by coupling with TMSCH2MgCl in the presence of
nickel() bisacetylacetonate8,12 furnished the cyclisation sub-
strate (Z)-allylsilane 7. It was necessary to conduct the cross
coupling reaction at 0 ЊC using 2.5 equivalents of TMSCH2-
MgCl for approximately 10 min to reduce chlorohydrin form-
ation. Using these optimised conditions, with 20 mol% of
nickel catalyst, the required epoxy allylsilane 7 was isolated
in 54% yield.
Conclusion
The synthesis of decalin subunit 2, using a biomimetic epoxy-
olefin cyclisation of enantiomerically pure allylsilane 7, was
achieved in 11 steps from geraniol, thus completing the formal
synthesis of (ϩ)-pyripyropene A 1. The shorter synthetic
route to 2, via cyclisation of the unprotected epoxy alcohol 6,
proved unsuccessful, as treatment with Lewis acids resulted in
monocyclisation or no cyclisation at all.
Experimental
Optical rotations were measured on a Perkin-Elmer 141 or
Treatment of the allylsilane 7 with BF3ؒOEt2 (optimum Lewis
acid) at room temperature gave the required decalin in 54%
yield as a 3:2 mixture of epimeric hydroxy esters 25. Other
Lewis acids e.g. SnCl4 or MeAlCl2 resulted in chlorohydrin
formation rather than cyclisation. All that remained to com-
plete the formal synthesis was isomerisation of the exocyclic
double bond and benzylation of the free alcohol.
an AA-10 polarimeter. Values are given in 10Ϫ1 deg cm2 gϪ1
.
Elemental analyses were performed using a Perkin-Elmer 2400
CHN elemental analyser. Infrared spectra were recorded on a
Perkin-Elmer 157G spectrophotometer. Nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker AC-250
FT spectrophotometer supported by an Aspect 4000 data
system and a Bruker WH-400 spectrophotometer supported
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321
3317

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by an Aspect 2000 data system. The chemical shifts (δH) were
recorded on the δ scale and were measured relative to the
residual proton signal of the deuterated solvent. J values are
given in Hz. Chemical shifts (δC) are quoted in ppm referenced
to the appropriate solvent peak and are assigned as s, d, t, q
for C, CH, CH2, CH3. Degenerate peaks are prefixed by the
number of carbons. Mass spectra were obtained using either a
Kratos MS 25 or MS 80 spectrometer supported by a DS 55
data system. High resolution mass spectra were obtained using
a Kratos MS 80 spectrometer supported by a DS 90 data
system. Chemical ionisation used ammonia as the reagent.
Thin layer chromatography (TLC) was performed on Merck
5554 60F silica gel coated plates and BDH silica (mesh 40–63)
was used for column chromatography. Petrol refers to light
petroleum (bp 40–65 ЊC) and ether refers to diethyl ether.
Where necessary, solvents and reagents were dried and distilled
before use. Boron trifluoride–diethyl ether was purified by the
addition of ca. 5% ether and distillation at reduced pressure
from calcium hydride. THF was refluxed over potassium
benzophenone ketyl under a nitrogen atmosphere until anhy-
drous. Diethyl ether was distilled from sodium benzoquinone
ketyl under an atmosphere of nitrogen. Dichloromethane was
distilled from calcium hydride.
an atmosphere of nitrogen was added anhydrous nickel()
acetylacetonate (450 mg, 1.75 mmol). The resulting dark-brown
mixture was stirred for 5 min before a solution of enol
phosphate 11 (3.54 g, 8.76 mmol) in diethyl ether (170 mL)
was added slowly. The reaction was stirred for 1 h at room
temperature before being quenched by careful addition of
1 M hydrochloric acid (until acidic). After dilution with diethyl
ether (150 mL), the solution was washed with 1 M hydrochloric
acid (100 mL), brine (2 × 100 mL), dried (MgSO4), and concen-
trated in vacuo. Purification by flash chromatography (silica gel,
20% EtOAc–petrol) afforded the allylsilane 12 (1.47 g, 50%)
as a yellow oil. Rf 0.24 (20% EtOAc–petrol) (Found: C, 67.3;
H, 10.0. C19H34SiO3 requires C, 67.5; H, 10.1%); νmax/cmϪ1 (thin
film) 3064 (OH), 2953 (CH), 1707 (C᎐O, ester), 1623 (C᎐C);
᎐
᎐
δH (250 MHz; CDCl3) 0.04 (9 H, s, 3 × SiCH3), 1.59 (3 H,
s, CH C᎐C), 1.65 (3 H, s, CH C᎐C), 1.98–2.18 (8 H, m,
᎐
᎐
3
3
4 × CH C᎐C), 2.41 (2 H, s, CH TMS), 3.65 (3 H, s, CO CH ),
᎐
2
2
2
3
3.98 (2 H, s, CH OH), 5.09 (1 H, t, J 7.0, CH᎐C), 5.37 (1 H, t,
᎐
2
J 7.0, CH᎐C(Me)CH OH), 5.53 (1 H, s, CHCO CH ); δ (63
᎐
2
2
3
C
MHz; CDCl3) Ϫ0.9 (3 × q), 13.6 (q), 16.0 (q), 26.1 (2 × t), 26.4
(t), 39.2 (t), 40.5 (t), 50.5 (q), 68.7 (t), 111.1 (d), 123.2 (d), 125.6
(d), 134.8 (s), 135.8 (s), 164.4 (s), 167.7 (s); m/z (EI) 338 (Mϩ,
4%), 323 (5), 305 (5), 253 (32), 149 (95), 107 (34), 73 (100)
(Found: Mϩ, 338.2286. C19H34SiO3 requires M 338.2277).
Preparation of methyl (2Z,6E,10E)-3-[(diethoxyphosphoryl)-
oxy]-12-hydroxy-7,11-dimethyldodeca-2,6,10-trienoate 11
Preparation of methyl (2Z,6E)-9-[(2S,3S)-3-(hydroxymethyl)-
3-methyloxiran-2-yl]-7-methyl-3-[(trimethylsilyl)methyl]nona-
2,6-dienoate 6
To selenium dioxide (55 mg, 0.50 mmol) and salicylic acid
(135 mg, 0.99 mmol) in dry dichloromethane (6 mL), chilled in
an ice–water bath, was added tert-butyl hydroperoxide (7.9 mL
of a 5 M solution in decane, 39.7 mmol) in one portion. To this
mixture was added a solution of the known enol phosphate
1010 (3.85 g, 9.92 mmol) in dry dichloromethane (6 mL) over
5 min. The resulting colourless solution was stirred for 25 h at
room temperature. The solution was diluted with dichloro-
methane (15 mL) and added to a solution of ferrous sulfate
heptahydrate (9 g, 32.5 mmol) in water (100 mL) at 0 ЊC. The
two-phase mixture was stirred for 30 min then separated.
The aqueous phase was extracted with dichloromethane (3 ×
30 mL). The organic layers were combined and washed with
1 M NaOH (50 mL), water (50 mL), brine (50 mL), dried
(MgSO4), and concentrated in vacuo. The reaction mixture was
dissolved in ice cold ethanol (30 mL), and NaBH4 (0.56 g, 14.88
mmol) was carefully added. Stirring continued for 2 h after the
addition, then the reaction was quenched by the addition of
1 M HCl (20 mL). The solution was poured into water (20 mL)
and extracted with dichloromethane (3 × 50 mL). The com-
bined organic extracts were washed with brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, 60% EtOAc–
petrol) to yield the allylic alcohol 11 (1.77 g, 44%) as a pale
yellow oil. Rf 0.16 (60% EtOAc–petrol) (Found: C, 56.5; H, 8.3.
C19H33PO7 requires C, 56.4; H, 8.2%); νmax/cmϪ1 (thin film) 3602
An oven dried two necked round-bottomed flask equipped with
a magnetic stir bar and a pressure equalising addition funnel
was charged with 480 mg of 3 Å powdered, activated molecular
sieves and dichloromethane (15 mL). The flask was cooled
to Ϫ20 ЊC before ()-(ϩ)-diethyl tartrate (49 µL, 0.29 mmol)
and titanium isopropoxide (53 µL, 0.18 mmol) were added
sequentially with stirring. The reaction mixture was stirred at
Ϫ20 ЊC as tert-butyl hydroperoxide (1.07 mL of a 5 M solution
in decane, 5.37 mmol) was added through the addition funnel
at a moderate rate (over ca. 5 min). The resulting mixture was
stirred at Ϫ20 ЊC for 30 min. The allylic alcohol 12 (1.21 g, 3.58
mmol), dissolved in dichloromethane (5 mL), was then added
dropwise through the same addition funnel over a period of
10 min. The reaction mixture was stirred at Ϫ20 ЊC for 6 h and
then treated with a solution of triethanolamine (48 µL, 0.36
mmol) in dichloromethane (5 mL). The solution was stirred for
30 min then filtered through a ca. 1.5 cm pad of flash silica gel
covered with Celite. The filter cake was rinsed with ethyl acetate
(100 mL) and the filtrate was concentrated in vacuo. Purific-
ation by flash chromatography (silica gel, 20% EtOAc–petrol)
afforded the epoxide 6 (887 mg, 70%, 90% ee) as a yellow oil.
[α]D22 Ϫ8.2 (c 6.25 in CH2Cl2); Rf 0.13 (20% EtOAc–petrol); νmax
cmϪ1 (thin film) 3593 (br, OH), 2954 (CH), 1708 (C᎐O, ester),
/
᎐
1623 (C᎐C); δ (250 MHz; CDCl3) 0.02 (9 H, s, 3 × SiCH3),
᎐
H
(OH), 2984 (CH), 1729 (C᎐O, ester), 1666 (C᎐C), 1272 (P᎐O),
᎐
᎐
᎐
1.25 (3 H, s, CH COC), 1.59 (3 H, s, CH C᎐CH), 1.62–1.68
᎐
3
3
1035 (P–O–C); δH (250 MHz; CDCl3) 1.34 (6 H, t, J 7.0,
2 × OCH CH ), 1.59 (3 H, s, CH C᎐C), 1.62 (3 H, s, CH C᎐C),
(2 H, m, CH CHO), 1.99–2.21 (6 H, m, 3 × CH C᎐C), 2.38
᎐
2
2
᎐
᎐
3
2
3
3
(2 H, s, CH2TMS), 2.99 (1 H, t, J 6.1, CHOC), 3.48–3.67 (2 H,
m, CH OH), 3.62 (3 H, s, CO CH ), 5.12 (1 H, t, J 6.7, CH᎐C),
1.97–2.47 (8 H, m, 4 × CH C᎐C), 3.67 (3 H, s, CO CH ), 3.95
᎐
2
2
3
᎐
2
2
3
(2 H, s, CH2OH), 4.23 (4 H, quint, J 7.0, 2 × OCH2CH3), 5.07
(1 H, t, J 7.0, CH᎐C), 5.32 (1 H, s, CHCO Me), 5.32 (1 H, m,
5.50 (1 H, s, CHCO2CH3); δC (63 MHz; CDCl3) Ϫ0.8 (3 × q),
14.2 (q), 16.0 (q), 26.1 (t), 26.4 (t), 26.7 (t), 36.2 (t), 40.5 (t), 50.5
(q), 59.8 (d), 60.9 (s), 65.4 (t), 111.1 (d), 123.8 (d), 135.1 (s),
164.1 (s), 167.7 (s); m/z (EI) 354 (Mϩ, 6%), 339 (25), 323 (20),
253 (43), 211 (25), 186 (45), 149 (100), 107 (65), 82 (60), 73 (100)
(Found: Mϩ, 354.2230. C19H34SiO4 requires M 354.2226).
᎐
2
CH᎐C(Me)CH OH); δ (63 MHz; CDCl3) 13.7 (q), 16.0
᎐
2
C
(2 × q), 16.1 (q), 24.8 (t), 25.9 (t), 35.1 (t), 39.1 (t), 51.1 (q), 64.8
(t), 64.9 (t), 68.7 (t), 104.8 (d), 122.1 (d), 125.3 (d), 135.0
(s), 136.6 (s), 161.5 (s), 164.3 (s); m/z (EI) 404 (Mϩ, 2%), 386 (3),
252 (20), 220 (24), 155 (100), 127 (23), 99 (35) (Found: Mϩ,
404.1962. C19H33PO7 requires M 404.1964).
Preparation of (2S,3S)-3-[(E)-5-bromo-3-methylpent-3-enyl]-2-
methyl-2-(benzyloxymethyl)oxirane 21
To a solution of the known allylic alcohol 2015 (294 mg, 1.07
mmol) and triethylamine (0.25 mL, 1.82 mmol) in tetrahydro-
furan (4 mL) at Ϫ78 ЊC was added methanesulfonyl chloride
Preparation of methyl (2Z,6E,10E)-12-hydroxy-7,11-dimethyl-
3-[(trimethylsilyl)methyl]dodeca-2,6,10-trienoate 12
To a solution of trimethylsilylmethylmagnesium chloride (52.6
mL of a 1 M solution in diethyl ether, 52.6 mmol) under
3318
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321

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(0.12 mL, 1.60 mmol) over 10 min. After the addition was
complete, the reaction was maintained at Ϫ78 ЊC and stirred
for a further 60 min during which time a white precipitate
had formed. A solution of anhydrous lithium bromide (0.28 g,
3.21 mmol) in acetone (2 mL) was then added and the resulting
suspension was stirred at Ϫ78 ЊC for 40 min. The suspension
was filtered through a pad of Celite followed by in vacuo con-
centration of the filtrate. The residue was diluted with ethyl
acetate (20 mL) and water (10 mL). After separation, the
aqueous layer was extracted with ethyl acetate (3 × 20 mL)
and the combined organic extracts were washed with saturated
aqueous sodium hydrogen carbonate (5 × 30 mL), dried
(MgSO4), and concentrated. Purification by flash chrom-
atography (silica gel, 15% EtOAc–petrol) afforded the allylic
bromide 21 (308 mg, 79% (ϩ7% allylic chloride)) as a colourless
oil. [α]D22 ϩ9.1 (c 1.54 in CH2Cl2); Rf 0.30 (15% EtOAc–petrol);
νmax/cmϪ1 (thin film) 2968 (CH), 1657 (C᎐C); δ (250 MHz;
was added triethylamine (0.55 mL, 3.93 mmol). The mixture
was cooled to Ϫ78 ЊC, and a solution of boron trifluoride–
diethyl ether (0.98 mL, 7.75 mmol) in dichloromethane (25 mL)
was added over a period of 2 h. The resulting solution was
allowed to stir for a further 2 h at Ϫ78 ЊC and then poured into
ethyl acetate (200 mL) and saturated aqueous sodium hydrogen
carbonate (200 mL). The organic phase was separated, washed
with 0.1 M hydrochloric acid (100 mL) and brine (100 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash
chromatography (silica gel, 20% EtOAc–petrol) afforded the
oxacycle 23 (291 mg, 61%) as a pale yellow oil. [α]D22 Ϫ13.9 (c 0.58
in CH2Cl2); Rf 0.50 (50% EtOAc–petrol); νmax/cmϪ1 (thin film)
3496 (br, OH), 2946 (CH), 1739 (C᎐O, ester), 1684 (C᎐C);
᎐
᎐
δH (250 MHz; CDCl3) 0.88 (3 H, s, CH3CO), 1.18 (3 H, s,
CH3C), 1.49–2.00 (7 H, m, CH2CHOH, CH2CH2CHOH,
CHCH CH᎐C, CHCH CH᎐C), 2.95 (2 H, br s, CH CO Me),
᎐
᎐
2
2
2
2
3.26 (1 H, d, J 8.6, CHHOBn), 3.34 (1 H, br s, OH), 3.44 (1 H,
d, J 8.6, CHHOBn), 3.66 (3 H, s, CO2CH3), 3.73 (1 H, dd,
J 11.1 and 4.1, CHOH), 4.47 (1 H, d, J 12.2, OCHHPh), 4.53
᎐
H
CDCl3) 1.33 (3 H, s, CH3COC), 1.60–1.80 (2 H, m, CH2-
CHOC), 1.74 (3 H, s, CH C᎐CH), 2.10–2.30 (2 H, m,
᎐
3
CH C(Me)᎐CH), 2.85 (1 H, t, J 6.4, CHOC), 3.42 (1 H, d,
(1 H, d, J 12.2, OCHHPh), 4.58 (1 H, dd, J 2.6 and 2.0, C᎐CH),
᎐
᎐
2
J 11.0, CHHOBn), 3.51 (1 H, d, J 11.0, CHHOBn), 3.99 (2 H,
d, J 8.5, CH2Br), 4.51 (1 H, d, J 11.9, OCHHPh), 4.57 (1 H, d,
J 11.9, OCHHPh), 5.57 (1 H, t, J 8.5, CHCH2Br), 7.27–7.40
(5 H, m, Ph); δC (63 MHz; CDCl3) 14.6 (q), 16.0 (q), 26.4 (t),
29.2 (t), 36.2 (t), 60.0 (s), 60.3 (d), 73.2 (t), 74.6 (t), 121.2 (d),
127.7 (3 × d), 128.4 (2 × d), 138.1 (s), 142.3 (s); m/z (CI)
356 (Mϩ ϩ NH4, 100%), 312 (35), 259 (25), 151 (30), 111 (30)
(Found: Mϩ, 339.0974. C17H23O2Br requires M 339.0960).
7.24–7.40 (5 H, m, Ph); δC (63 MHz; CDCl3) 11.0 (q), 19.2 (q),
19.3 (t), 27.1 (t), 37.2 (t), 40.1 (t), 41.5 (s), 42.3 (d), 51.9 (q), 73.7
(t), 76.0 (d), 76.0 (s), 79.3 (t), 97.8 (d), 127.6 (d), 127.9 (2 × d),
128.5 (2 × d), 137.7 (s), 145.3 (s), 171.0 (s); m/z (EI) 374
(Mϩ, 20%), 265 (20), 149 (20), 91 (100), 55 (25) (Found:
Mϩ, 374.2093. C22H30O5 requires M 374.2086).
Preparation of methyl (2Z,6E)-3-[(diethoxyphosphoryl)oxy]-7-
methyl-9-[(2S,3S)-3-methyl-3-(benzyloxymethyl)oxiran-2-yl]-
nona-2,6-dienoate 24
Preparation of methyl (E)-7-methyl-9-[(2S,3S)-3-methyl-3-
(benzyloxymethyl)oxiran-2-yl]-3-oxonon-6-enoate 22
A solution of the β-keto ester 22 (100 mg, 0.27 mmol) in diethyl
ether (1 mL) was added to a suspension of sodium hydride
(21 mg of a 60% oil dispersion, 0.54 mmol) in diethyl ether
(2 mL) under an atmosphere of nitrogen at 0 ЊC. After stirring
for 20 min, diethyl phosphorchloridate (58 µL, 0.40 mmol)
was introduced and stirring was continued for 2.5 h at room
temperature. The reaction mixture was stirred with excess
ammonium chloride, filtered through Celite, and concentrated
in vacuo. Purification by flash chromatography (silica gel,
40% EtOAc–petrol) afforded the enol phosphate 24 (127 mg,
93%) as a yellow oil. [α]D22 Ϫ2.9 (c 2.55 in CH2Cl2); Rf 0.15
(40% EtOAc–petrol); νmax/cmϪ1 (thin film) 2985 (CH), 1728
Sodium hydride (256 mg of a 60% oil dispersion, 6.40 mmol)
was stirred in tetrahydrofuran (10 mL) at 0 ЊC under an atmo-
sphere of nitrogen. Methyl acetoacetate (0.57 mL, 5.33 mmol)
was added dropwise and the colourless solution was stirred
at 0 ЊC for 10 min. To this solution was added n-butyllithium
(3.67 mL of a 1.6 M solution in hexane, 5.87 mmol) dropwise
and the yellow–orange solution was stirred for a further 10 min.
To this solution was then added a solution of the allylic
bromide 21 (0.90 g, 2.67 mmol) in tetrahydrofuran (8 mL) and
the reaction was allowed to warm to room temperature with
stirring. The reaction was left to stir for 17 h before being
quenched with 1 M hydrochloric acid (8 mL) and ethyl acetate
(10 mL). After separation, the aqueous layer was extracted with
ethyl acetate (4 × 30 mL) and the combined organic layers were
washed with water (3 × 25 mL), dried (MgSO4), and concen-
trated in vacuo. Purification by flash chromatography (silica
gel, 20% EtOAc–petrol) afforded the β-keto ester 22 (776 mg,
78%) as a yellow oil. [α]D22 Ϫ3.7 (c 0.54 in CH2Cl2); Rf 0.45
(40% EtOAc–petrol) (Found: C, 70.3; H, 8.3. C22H30O5 requires
(C᎐O, ester), 1666 (C᎐C), 1281 (P᎐O), 1034 (P–O–C); δ (250
᎐
᎐
᎐
H
MHz; CDCl3) 1.30 (3 H, s, CH3COC), 1.34 (6 H, J 7.0,
2 × OCH2CH3), 1.58–1.66 (2 H, m, CH2CHOC), 1.61 (3 H, s,
CH C᎐CH), 2.00–2.46 (6 H, m, CH C(Me)᎐CH, CH CH᎐C,
᎐
᎐
᎐
3
2
2
CH CH CH᎐C), 2.82 (1 H, t, J 6.4, CHOC), 3.39 (1 H, d,
᎐
2
2
J 10.7, CHHOBn), 3.48 (1 H, d, J 10.7, CHHOBn), 3.66 (3 H,
s, CO2CH3), 4.23 (4 H, quint, J 7.0, 2 × OCH2CH3), 4.49
(1 H, d, J 11.9, OCHHPh), 4.56 (1 H, d, J 11.9, OCHHPh),
5.12 (1 H, t, J 7.0, CH᎐C), 5.32 (1 H, s, CHCO Me), 7.25–
C, 70.6; H, 8.0%); νmax/cmϪ1 (thin film) 2955 (CH), 1748 (C᎐O,
᎐
᎐
2
ester), 1717 (C᎐O), 1629 (C᎐C); δ (250 MHz; CDCl3) 1.31
7.35 (5 H, m, Ph); δC (63 MHz; CDCl3) 14.4 (q), 16.0 (q),
16.1 (2 × q), 24.8 (t), 26.8 (t), 35.1 (t), 36.2 (t), 51.1 (q), 59.8
(s), 60.5 (d), 64.7 (t), 64.8 (t), 73.1 (t), 74.7 (t), 104.9 (d),
122.4 (d), 127.6 (3 × d), 128.3 (2 × d), 136.1 (s), 138.2 (s),
161.5 (s), 164.3 (s); m/z (CI) 510 (Mϩ, 0.5%), 319 (20), 155
(82), 91 (100) (Found: Mϩ, 510.2389. C26H39PO8 requires
M 510.2383).
᎐
᎐
H
(3 H, s, CH3COC), 1.58–1.67 (2 H, m, CH2CHOC), 1.61 (3 H, s,
CH C᎐CH), 2.00–2.31 (4 H, m, CH C(Me)᎐CH, CH CH᎐C),
᎐
᎐
᎐
3
2
2
2.54 (2 H, t, J 7.3, CH C᎐O), 2.82 (1 H, t, J 6.4, CHOC), 3.40
᎐
2
(1 H, d, J 11.0, CHHOBn), 3.41 (2 H, s, CH2CO2Me), 3.48
(1 H, d, J 11.0, CHHOBn), 3.71 (3 H, s, CO2CH3), 4.50 (1 H, d,
J 11.9, OCHHPh), 4.56 (1 H, d, J 11.9, OCHHPh), 5.10 (1 H,
t, J 7.2, CH᎐C), 7.25–7.35 (5 H, m, Ph); δ (63 MHz; CDCl3)
᎐
C
14.5 (q), 16.0 (q), 22.1 (t), 26.8 (t), 36.3 (t), 42.9 (t), 49.1 (t), 52.3
(q), 59.8 (s), 60.6 (q), 73.1 (t), 74.8 (t), 122.8 (d), 127.6 (3 × d),
128.4 (2 × d), 135.7 (s), 138.2 (s), 167.6 (s), 202.3 (s); m/z (CI)
392 (Mϩ ϩ NH4, 100%), 244 (20), 227 (10), 108 (10) (Found:
Mϩ ϩ NH4, 392.2443. C22H34NO5 requires M 392.2437).
Preparation of methyl (2Z,6E)-7-methyl-9-[(2S,3S)-3-methyl-3-
(benzyloxymethyl)oxiran-2-yl]-3-[(trimethylsilyl)methyl]nona-
2,6-dienoate 7
To
a solution of trimethylsilylmethylmagnesium chloride
(1.26 mL of a 0.87 M solution in diethyl ether, 1.10 mmol) at
0 ЊC under an atmosphere of nitrogen was added anhydrous
nickel() acetylacetonate (23 mg, 0.09 mmol). The resulting
dark-brown mixture was stirred for 5 min before a solution of
enol phosphate 24 (224 mg, 0.44 mmol) in diethyl ether (11 mL)
was added slowly. The reaction was stirred at 0 ЊC for 10 min
Cyclisation of methyl (E)-7-methyl-9-[(2S,3S)-3-methyl-3-
(benzyloxymethyl)oxiran-2-yl]-3-oxonon-6-enoate 22
To a solution of β-keto ester 22 (474 mg, 1.27 mmol) in dry
dichloromethane (12 mL), toluene (12 mL), hexane (12 mL),
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321
3319

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before being quenched by careful addition of 1 M hydrochloric
acid (until acidic). After dilution with diethyl ether (15 mL), the
solution was washed with 1 M hydrochloric acid (10 mL),
brine (2 × 10 mL), dried (MgSO4), and concentrated in vacuo.
Purification by flash chromatography (silica gel, 10% EtOAc–
petrol) afforded the allylsilane 7 (105 mg, 54%) as a yellow oil.
[α]D22 Ϫ2.56 (c 5.2 in CH2Cl2); Rf 0.50 (20% EtOAc–petrol);
νmax/cmϪ1 (thin film) 2953 (CH), 1708 (C᎐O, ester), 1623 (C᎐C);
(silica gel, 5% EtOAc–petrol) afforded the decalin 2 (11 mg,
51%) as a colourless oil. [α]D22 ϩ76.4 (c 0.45 in CHCl3) [lit.,4 ϩ81
(c 0.5 in CHCl3)]; Rf 0.18 (5% EtOAc–petrol); νmax/cmϪ1
(CHCl ) 2949 (CH), 1713 (C᎐O, ester); δ (250 MHz; CDCl3)
᎐
3
H
0.73 (3 H, s, CH3), 1.22 (3 H, s, CH3), 1.37–1.93 (7 H, m,
CH2CHOBn, CH2CH2CHOBn, CH2CH2CH, CHCH2CH2),
1.61 (3 H, s, C᎐CCH ), 2.05 (2 H, m, CH C(Me)᎐C), 3.13 (1 H,
᎐
᎐
3
2
d, J 9.1, CHHOBn), 3.36 (1 H, d, J 9.1, CHHOBn), 3.57 (1 H,
dd, J 11.0 and 4.6, CHOBn), 3.72 (3 H, s, CO2CH3), 4.28
(1 H, d, J 12.2, OCHHPh), 4.36 (1 H, d, J 11.9, OCHHPh),
4.41 (1 H, d, J 12.2, OCHHPh), 4.59 (1 H, d, J 11.9, OCHHPh),
7.29 (10 H, m, 2 × Ph) [lit.,4 δH (270 MHz; CDCl3) 0.74 (3 H, s),
1.22 (3 H, s), 0.97–1.92 (7 H, complex m), 1.62 (3 H, s), 2.07
(2 H, m), 3.14 (1 H, d, J 9.1), 3.37 (1 H, d, J 9.1), 3.57 (1 H, dd,
J 11.5 and 4.6), 3.73 (3 H, s), 4.29 (1 H, d, J 12.3), 4.32 (1 H,
d, J 11.9), 4.40 (1 H, d, J 12.3), 4.60 (1 H, d, J 11.9), 7.29
(10 H, m)]; δC (63 MHz; CDCl3) 13.2 (q), 17.7 (t), 20.9 (2 × q),
22.8 (t), 31.9 (t), 34.5 (t), 36.4 (s), 42.2 (d), 42.5 (s), 51.1 (q),
71.4 (t), 71.9 (t), 72.9 (t), 79.1 (d), 127.3 (d), 127.4 (d), 127.6
(4 × d), 128.2 (4 × d), 132.9 (s), 137.9 (s), 138.8 (s), 139.3 (s),
170.9 (s); m/z (EI) 462 (Mϩ, 2%), 432 (10), 283 (12), 248 (37),
233 (17), 91 (100) (Found: Mϩ, 462.2752. C30H38O4 requires
M 462.2770).
᎐
᎐
δH (250 MHz; CDCl3) 0.04 (9 H, s, 3 × SiCH3), 1.32 (3 H, s,
CH COC), 1.61 (3 H, s, CH C᎐CH), 1.61–1.69 (2 H, m,
᎐
3
3
CH CHOC), 2.04–2.17 (6 H, m, CH C(Me)᎐CH, CH CH᎐C,
᎐
᎐
2
2
2
CH CH CH᎐C), 2.40 (2 H, s, CH TMS), 2.84 (1 H, t, J 6.1,
᎐
2
2
2
CHOC), 3.41 (1 H, d, J 11.0, CHHOBn), 3.50 (1 H, d, J 11.0,
CHHOBn), 3.64 (3 H, s, CO2CH3), 4.51 (1 H, d, J 12.2,
OCHHPh), 4.58 (1 H, d, J 12.2, OCHHPh), 5.14 (1 H, t, J 7.0,
CH᎐C), 5.52 (1 H, s, CHCO Me), 7.25–7.35 (5 H, m, Ph); δ (63
᎐
2
C
MHz; CDCl3) Ϫ0.8 (3 × q), 14.5 (q), 16.1 (q), 26.2 (t), 26.5 (t),
26.9 (t), 36.3 (t), 40.5 (t), 50.5 (q), 59.9 (s), 60.6 (d), 73.1 (t), 74.8
(t), 111.1 (d), 123.7 (d), 127.6 (3 × d), 128.4 (2 × d), 135.2 (s),
138.1 (s), 164.2 (s), 167.7 (s); m/z (EI) 444 (Mϩ, 2.5%), 429 (7),
253 (25), 186 (28), 149 (43), 91 (100) (Found: Mϩ, 444.2682.
C26H40SiO4 requires M 444.2696).
Preparation of methyl (4aS,5R,6S,8aS)-6-hydroxy-5,8a-di-
methyl-2-methylene-5-(benzyloxymethyl)perhydronaphthalene-
1-carboxylate 25
Acknowledgements
We thank the EPSRC and SmithKline Beecham for financial
support and Meng Fang Wang for initial studies.
To a solution of epoxy allylsilane 7 (120 mg, 0.27 mmol) in
dichloromethane (9 mL) was slowly added BF3ؒOEt2 (41 µL,
0.32 mmol) at room temperature. The reaction mixture was
stirred for 10 min then quenched with brine (2 mL). The
organic layer was diluted with dichloromethane (10 mL),
washed with brine (2 × 10 mL), dried (MgSO4), and concen-
trated in vacuo. Purification by flash chromatography (silica gel,
20% EtOAc–petrol) afforded the bicyclic alcohol 25 (54 mg,
54%) as a yellow oil. [α]D22 ϩ8.1 (c 2.95 in CH2Cl2); Rf 0.16 (20%
EtOAc–petrol); νmax/cmϪ1 (thin film) 3500 (br, OH), 2949 (CH),
References
1 H. Tomoda, N. Tabata, D.-J. Yang, H. Takayanagi, H. Nishida and
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S. Omura, J. Antibiotics, 1995, 48, 495; H. Tomoda, Y.-K. Kim,
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H. Nishida, R. Masuma and S. Omura, J. Antibiotics, 1994, 47, 148;
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S. Omura, H. Tomoda, Y.-K. Kim and H. Nishida, J. Antibiotics,
1993, 46, 1168; Y.-K. Kim, H. Tomoda, H. Nishida, T. Sunazuka,
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R. Obata and S. Omura, J. Antibiotics, 1994, 47, 154; T. Sunazuka
1731 (C᎐O, ester), 1684 (C᎐C); δ (250 MHz; CDCl3) 0.89
and T. Nagamitsu, J. Synth. Org. Chem. Jpn., 1988, 56, 478.
2 D. R. Sliskovic and A. D. White, Trends Pharmacol. Sci., 1991, 12,
194.
᎐
᎐
H
(1.5 H, s, CH3), 0.94 (1.5 H, s, CH3), 0.95 (1.5 H, s, CH3), 1.08
(1.5 H, s, CH3), 1.21–1.68 (7 H, m, CH2CHOH, CH2CH2-
CHOH, CH2CH2CH, CHCH2CH2), 1.95–2.62 (2 H, m, CH2-
CH2CCH2), 2.76 (1 H, s, CHCO2Me), 3.20 (0.5 H, d, J 8.9,
CHHOBn), 3.34 (0.5 H, d, J 8.9, CHHOBn), 3.47 (0.5 H, d,
J 8.9, CHHOBn), 3.56 (0.5 H, d, J 8.9, CHHOBn), 3.62 (1.5 H,
s, CO2CH3), 3.64 (1.5 H, s, CO2CH3), 3.60–3.71 (1 H, m,
CHOH), 4.46 (1 H, d, J 12.2, OCHHPh), 4.54 (1 H, d, J 12.2,
3 K. A. Parker and L. Resnick, J. Org. Chem., 1995, 60, 5726.
4 A. B. Smith III, T. Nagamitsu, T. Sunazuka, R. Obata, H. Tomoda,
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H. Tanaka, Y. Harigaya and S. Omura, J. Org. Chem., 1995, 60,
8126.
5 For a review, see: (a) S. K. Taylor, Org. Prep. Proc. Int., 1992, 24,
247. For recent examples, see: (b) E. J. Corey and M. Sodeoka,
Tetrahedron Lett., 1991, 32, 7005; (c) E. J. Corey, G. Luo and L. S.
Lin, J. Am. Chem. Soc., 1997, 119, 9927; (d) E. J. Corey, G. Luo and
L. S. Lin, Angew. Chem., Int. Ed., 1998, 37, 1126; for mechanistic
studies, see: (e) E. J. Corey and D. D. Staas, J. Am. Chem. Soc., 1998,
120, 3526.
6 B. K. Sharpless, Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko
and H. Masamune, J. Am. Chem. Soc., 1987, 109, 5765.
7 V. K. Aggarwal, P. A. Bethel and R. Giles, Chem. Commun., 1999,
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8 L. Weiler and R. J. Armstrong, Can. J. Chem., 1986, 64, 584.
9 L. Weiler and S. N. Huckin, J. Am. Chem. Soc., 1974, 96, 1082.
10 L. Weiler and F.-W. Sum, Can. J. Chem., 1979, 57, 1431.
11 K. B. Sharpless and M. A. Umbreit, J. Am. Chem. Soc., 1977, 99,
5526.
12 M. Kumada, T. Hayashi and Y. Katsuro, Tetrahedron Lett., 1980,
21, 3915.
OCHHPh), 4.66 (0.5 H, s, C᎐CHH), 4.73 (0.5 H, s, C᎐CHH),
᎐
᎐
4.83 (1 H, s, C᎐CHH), 7.29–7.39 (5 H, m, Ph); δ (63 MHz;
᎐
C
CDCl3) 12.2 (q), 14.6 (q), 21.1 (q), 22.9 (t), 23.1 (t), 26.3 (t), 26.5
(t), 31.7 (t), 35.6 (t), 35.8 (t), 36.6 (t), 37.9 (s), 38.9 (s), 39.8 (d),
41.9 (s), 42.3 (s), 48.3 (d), 51.1 (q), 51.4 (q), 62.7 (q), 63.1 (q),
73.6 (t), 73.8 (t), 75.6 (d), 77.0 (d), 78.8 (t), 81.4 (t), 108.9 (t),
112.9 (t), 127.6 (2 × d), 127.8 (d), 128.5 (2 × d), 137.9 (s),
138.0 (s), 143.0 (s), 143.6 (s), 171.8 (s), 173.0 (s); m/z (EI) 373
(Mϩ ϩ H, 100%), 355 (75), 264 (42), 246 (80), 233 (37), 206
(35), 105 (33), 91 (82) (Found: Mϩ, 372.2314. C23H32O4 requires
M 372.2301).
Preparation of methyl (4aS,5R,6S,8aS)-2,5,8a-trimethyl-6-
(benzyloxy)-5-(benzyloxymethyl)-3,4,4a,5,6,7,8,8a-octahydro-
naphthalene-1-carboxylate 2
13 E. J. Corey, J. Lee and D. R. Liu, Tetrahedron Lett., 1994, 35, 9149.
14 (a) T. Frejd, L. Pettersson and G. Magnusson, Tetrahedron Lett.,
1987, 28, 2753; (b) M. E. Jung, Y. M. Cho and Y. H. Jung,
Tetrahedron Lett., 1996, 37, 3.
A solution of the bicyclic alcohol 25 (17 mg, 0.046 mmol)
in THF (0.7 mL) was treated with NaH (9 mg of a 60% oil
dispersion, 0.23 mmol) and the mixture was heated at reflux for
4 h. Benzyl bromide (27 µL, 0.23 mmol) was then added and the
reaction was maintained at reflux for a further 2 h, cooled, and
carefully quenched with water. The aqueous layer was extracted
with dichloromethane (3 × 5 mL) and the combined organic
extracts were washed with brine (10 mL), dried (MgSO4), and
concentrated in vacuo. Purification by flash chromatography
15 S. P. Tanis, Y.-H. Chuang and D. B. Head, J. Org. Chem., 1988, 53,
4929.
16 B. Ganem and L. J. Liotta, Tetrahedron Lett., 1989, 30, 4759.
17 F. E. Ziegler, S. I. Klein, U. K. Pati and T.-F. Wang, J. Am. Chem.
Soc., 1985, 107, 2730.
18 It was important to reduce the amount of allylic chloride present
in the reaction mixture as it was found to be inefficient in the
subsequent alkylation reaction.
19 Alternative conditions (CBr4, PPh3) resulted in lower yields of the
allylic bromide 21 and led to bromohydrin formation.
3320
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321

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20 β-Keto esters are known to cyclise through oxygen rather than
carbon, see: T. R. Hoye, A. J. Caruso and M. J. Kurth, J. Org.
Chem., 1981, 46, 3550; J. D. White, R. W. Skeean and G. L.
Trammell, J. Org. Chem., 1985, 50, 1939.
23 The recovered isomer 28 was enriched in one diastereomer after
2 h reflux with NaH. After 4 h reflux, the recovered isomer 28
appeared to be one diastereomer only, suggesting a difference in
deprotonation rates for the two diastereomeric esters.
24 J. Andrieux, D. H. R. Barton and H. Patin, J. Chem. Soc., Perkin
Trans. 1, 1977, 359.
21 From molecular modelling (SPARTAN) it was found that 27 was
lower in energy than the conjugated tetrasubstituted double bond
isomer 2.
22 By 1H NMR, 13C NMR, mass and IR analyses.
Paper 9/06589J
J. Chem. Soc., Perkin Trans. 1, 1999, 3315–3321
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