Total synthesis of the polyenoyltetramic acid polycephalin C

Article abstract of DOI:10.1016/S0040-4020(03)00816-0

The total synthesis of the polyenoyltetramic acid polycephalin C is described. Key steps of the synthesis include a double Swern oxidation, double Takai reaction and a double Stille reaction. In addition, the absolute stereochemistry of the ring junction

Full text of DOI:10.1016/S0040-4020(03)00816-0

Tetrahedron 59 (2003) 6955–6966
Total synthesis of the polyenoyltetramic acid polycephalin C
*
Deborah A. Longbottom, Angus J. Morrison, Darren J. Dixon and Steven V. Ley
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 2 April 2003; revised 25 April 2003; accepted 30 April 2003
Dedicated to K. C. Nicolaou in recognition of his receipt of the Tetrahedron Prize and his enormous contribution to the art and craft of Organic Synthesis
Abstract—The total synthesis of the polyenoyltetramic acid polycephalin C is described. Key steps of the synthesis include a double Swern
oxidation, double Takai reaction and a double Stille reaction. In addition, the absolute stereochemistry of the ring junction has been
determined by synthesis of both isomers and comparison of their CD spectra with natural polycephalin C.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
could be R,R or S,S we arbitrarily selected the S,S isomer as
the 0initial target. 00D0 isconnection between carbons C-50 and
C-6 and also C-2 and C-3000 led to two main fragments, the
stannylated dienoyltetramic acid 2 and the bis-iodide
intermediate 3. It was envisaged that stannane 2 would be
prepared from readily available thioester 4 and amino ester
5, fragments which had been utilised previously in our
syntheses of physarorubinic acid4a and erythroskyrine.4b
The tetramic acid (pyrrolidine-2,4-dione) ring system is a
key structural unit in many natural products.1 The spectrum
of biological activity displayed by these natural products is
remarkable in its diversity; it includes potent antibiotic,
antiviral and antiulcerative properties, cytotoxicity and
mycotoxicity, the inhibition of tumors as well as fungicidal
acitivity. In addition, other members of this class are
responsible for pigmentation of certain sponges and molds.1
To synthesise the bis-iodide 3 it was envisaged that starting
from cyclohexene diol 6, 1,4-dioxidation and a double Takai
reaction would provide this fragment rapidly. It was
expected that diol 6 would be prepared from Diels–Alder
adduct 7 via double bond manipulation and exhaustive
reduction (Scheme 1). With both fragments in hand a double
Stille coupling followed by TBS deprotection would then
give (300S,400S)-1 in a concise fashion.
A recently isolated member of this class of compounds is
polycephalin C 1.2 This fungal metabolite isolated from the
extracts of Physarum polycephalum is a bis(trienoyl)te-
tramic acid linked by an unusual asymmetric cyclohexene
ring (Fig. 1). The tetramic acid unit of each terminus is
derived from (S)-N-methyl serine and is linked by a fully
conjugated all-E-triene chain to the cyclohexene ring (Fig.
1). This unusual tetramic acid is thought to be one of several
metabolites responsible for the yellow colour of the wild-
type plasmodia P. polycephalum.2 Although the structure
elucidation paper 0h0 ad established that the relative configur-
ation at the 300,4 ring junction was trans the absolute
stereochemistry at these positions had not been established.
Hence, we initiated a total synthesis programme towards
this challenging molecule, with the goal of defining the
absolute structure of this molecule. We now wish to report
in full the details of this study.3
1.1. Retrosynthetic analysis
As the 300,400 ring junction configuration of polycephalin C 1
Keywords: natural product synthesis; tetramic acids; lactams; Takai
reaction; Swern oxidation.
*
Corresponding author. Tel.: þ44-1223-336442; fax: þ44-1223-336398;
e-mail: svl1000@cam.ac.uk
Figure 1. Polycephalin C.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00816-0

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D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
Scheme 1. Retrosynthetic analysis.
2. Results and discussion
triethylamine and reducing the amount of silver trifluoro-
acetate and purification of the reaction mixture on silica not
florosil† resulted in a clean and high yielding synthesis of
ketoamide 8.
2.1. Synthesis of dienoyltetramic acid 2
The two step sequence which leads to the formation of
dienoyltetramic acid 2 begins with a silver mediated
aminolysis reaction.5 This mild and selective reaction for
the formation of b-ketoamides had been applied success-
fully in our synthesis of physarorubinic acid4a and
erythroskyrine4b and accordingly we did not envisage any
difficulty with the synthesis of ketoamide 8 from thioester 4
and amino ester 5. However, to our surprise initial attempts
at the reaction gave only small amounts (30–40%) of
destannylated product 9 (Scheme 2) following column
chromatography on florisil.
Scheme 3. Reagents and conditions: (a) NaOMe, MeOH, 258C, 2 min,
90%.
The Dieckmann cyclisation of ketoamide 8 utilising sodium
methoxide in methanol proceeded as expected revealing the
dienoyltetramic acid 2 in an excellent 90% yield (Scheme 3).
With the tetramic acid portion in hand attention was turned
to the synthesis of bis-iodide 3.
The reaction conditions were therefore investigated, since
the only perceptible reason for destannylation to occur was
the presence of acid. Indeed, on increasing the amount of
2.2. Synthesis of bis-iodide 3
The starting point for the synthesis of bis-iodide 3 was a
chiral auxillary mediated Diels–Alder reaction, whereby
the two stereocentres would be created with high dia-
stereocontrol in a single step. The asymmetric Diels–Alder
reaction employed in this case combines the dienophile,
(þ)-dimenthyl fumarate 10, with 1,3-butadiene to yield a
trans disubstituted cyclohexene 7. This asymmetric reac-
tion, pioneered by Walborsky and perfected by Yamamoto
is reported to occur with excellent diastereoselectivity.6
Although (þ)-Dimenthyl fumarate 10 is commercially
available, due to the large quantities required for the
†
Scheme 2. Reagents and conditions: (a) 2 equiv. CF3CO2Ag, 2.5 equiv.
NEt3, THF, 08C, 2 h, 45% yield of 9, (b) 1 equiv. CF3CO2Ag, 5 equiv.
NEt3, THF, 08C, 20 min, 81% yield of 8.
Florosil is composed of silica, magnesium oxide and sodium sulfate, it is
thought that the aminolysis product may have been coordinating metal
ions and being lost in this way.

D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
6957
Scheme 4. Reagents and conditions: (a) p-toluenesulfonic acid·H2O,
toluene, reflux, 17 h, 90%, (b) morpholine, toluene, 1008C, 81%,
(c) Et2AlCl, butadiene, 2608C, 36 h, 73%.
proposed route, the dienophile was synthesised in two steps
from maleic anhydride (Scheme 4).7 (see Experimental)
With the dienophile in hand the low temperature Lewis acid
mediated Diels–Alder reaction was carried out to afford
exclusively the desired Diels–Alder adduct (R,R)-7 (d.e.
.95% by NMR) in a 73% yield (Scheme 4).
Scheme 5. Reagents and conditions: (a) PhSeCl, MeCN/H2O (13:1), room
temperature, 30 min, (b) PhSeBr, MeCN/H2O (15:1), 508C, 12 h, 75%,
(c) m-CPBA, CH2Cl2, 2308C, 5 min then Hu¨nigs base, 508C, 14 h, 92%
over 2 steps.
Having set the stereochemistry at the ring junction, double
bond transposition was then required. It was envisaged that
overall addition of selenic acid across the double bond and a
subsequent oxidation–elimination sequence would affect
the desired process.8
With mesylate 15 in hand, exhaustive reduction conditions
were then examined to prepare diol 6. Initial attempts at
carrying out this transformation using lithium aluminium
hydride were promising. Carrying out the reaction at 08C in
THF resulted in high yields (83–100%) and a pleasing 3:1
ratio of SN2/SN20 attack. A variety of other solvents were
then examined including ether, dimethoxyethane and
dioxane, but none of which increased the ratio of desired
diol 6 to undesired diol 16. Alternative reducing agents were
therefore tried and these included Super hydride, lithium
borohydride and K-selectride. All attempts utilising these
reagents either failed to increase the ratio of desired to
undesired or gave multicomponent reaction mixtures.
Initial attempts at this reaction utilising phenylselenium
chloride in a 13:1 MeCN/H2O mixture resulted only in
formation of the unwanted chloride 11. Unfortunately, this
material was not useful in the synthesis, as the subsequent
oxidation–elmination sequence would have given a mixture
of both desired and undesired alkenes.8a Therefore, the
reaction was repeated but this time utilising phenylselenium
bromide at elevated temperatures (508C). Pleasingly, it was
found that utilising these reaction conditions resulted in
clean conversion of alkene 7 to the desired hydroxyselenide
12 in good yield (Scheme 5). Subsequent oxidation with
m-CPBA at 2308C followed by heating to 508C in the
presence of Hu¨nigs base gave the desired allylic alcohol 13
in an excellent 92% overall yield (Scheme 5).
It is known that sodium borohydride in refluxing DMSO can
reduce esters and can also reduce sulfonate derivatives.10
Interestingly, it was found that the reduction of the esters did
not take place, even at elevated temperatures but that
mesylate reduction did occur in an encouraging 30:1 SN2/
SN20 ratio. In order to further improve this ratio a DMSO/
THF (1:1) solvent mixture was utilised thus permitting a
lowering of the reaction temperature. Utilising this system a
40:1 ratio in favour of SN2 attack could be achieved.
Unfortunately, on scale up of the reaction, yields were
greatly decreased from the initial 61% on a small scale
Having transposed the double bond, removal of the
hydroxyl group and reduction of the two ester functional-
ities was required. Obviously, the most efficient design of
the synthesis would carry out both of these transformations
simultaneously. To that end it was proposed that conversion
of the hydroxyl group to a leaving group and then carrying
out an exhaustive reduction would achieve this goal.
In the first instance the tosylate leaving group was selected
for this reaction. However, low temperature tosylation
proved ineffective and tosylation at elevated temperature
occurred but was followed by elimination to form diene 14
(Scheme 6). It was thought that the steric bulk of the tosylate
group was prohibiting the desired bond formation at low
temperature and that low temperature was key to preventing
elimination. Therefore, formation of the less bulky mesylate
15 was undertaken. However, at 08C, this attempted
mesylation also gave only diene 14 with only a small
amount of desired product. On the other hand, when the
reaction was carried out at lower temperature (2788C to
2158C) and quenched at low temperature the mesylate 15
could be formed in an excellent 87% yield (Scheme 6). At
this point crystals of suitable quality were grown for X-ray
crystallography and proved the absolute configuration of
mesylate 15.9
Scheme 6. Reagents and conditions: (a) p-toluenesulfonyl chloride,
pyridine, 408C, 6 h, 67%, (b) methanesulfonyl chloride, Et3N, CH2Cl2,
2788C to 2158C, 87%, (c) LiAlH4, THF, 2788C to room temperature,
85% overall yield (5:1 6/16), 64% 6.

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D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
acceptable 5:1 of separable diols in a combined 85% yield
and furnishing a 64% isolated yield of desired diol 6
(Scheme 6). Utilising this reaction sequence gram quantities
of diol 6 could be prepared.
At this point, the 1,4-oxidation of diol 6 was then
investigated and the Swern11 reaction selected as the
optimum method. However, initial attempts at the double
Swern oxidation were disappointing resulting in the
formation of a,b-unsaturated dialdehyde 17. However,
this problem could be overcome by replacement of
triethylamine with a more hindered base.12 Thus, Swern
oxidation with Hu¨nigs base, followed by a cold acidic
workup and washing with pH 7 buffer solution provided the
desired dialdehyde 18 in high yield and purity (Scheme 7).
The unstable nature of this compound meant that it was
freshly prepared for immediate use in the subsequent step,
formation of the Stille coupling partner 3.
Scheme 7. Reagents and conditions: (a) (COCl)2, DMSO, 2788C, 2 h then
NEt3, 2788C to 2108C, (b) (COCl)2, DMSO, 2788C, 1 h then iPr2NEt,
2788C to 08C, 15 min, 87%, (c) CrCl2, CHI3, 08C to room temperature, 2 h,
40%.
It was envisaged that a double Takai13 olefination reaction
could be used to install the required trans-double bond
geometry in the formation of bis-iodide 3. Upon reacting the
dialdehyde 18 under standard Takai reaction conditions we
were delighted to find that the desired bis-iodide 3 was the
major product of the reaction (.90% bis-trans product by
NMR) in a reasonable 40% yield. Thus bis-iodide 3 was
prepared from (þ)-dimenthyl fumarate in 7 steps in an
overall 9.8% yield. Having 00prepared the two fragments
required to construct (300S,4 S)-1 we then examined the
reaction required to join the two fragments, a double Stille14
coupling.
(50 mg) to only 43% when the reaction was carried out on
gram scale. Hence these reaction conditions were
abandoned.
Indeed, the best result obtained after these reaction
conditions had been investigated was a modification of the
initial reduction, using lithium aluminium hydride in THF.
By carrying out the reaction from 2788C to room
temperature, the SN2/SN20 ratio was increased to an
Scheme 8. Reagents and conditions: (a) 20 mol% [Pd(Pfur3)2Cl2], DMF, room temperature, 2 h, (b) 15 mol% [Pd(MeCN)2Cl2], DMF, room temperature, 1 h,
53%, (c) TFA/H2O, (9:1)£3, room temperature, 64%.

D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
6959
Figure 3. CD spectrum of (300R,400R)-1.
Figure 2. CD spectrum of (300S,400S)-1.
synthetic material were in excellent agreement with that
published in the literature and coupling constants from the
polyene chain indicate the all (E)-double bond geometry.
However, despite being of the correct sign, the optical
rotation was found to differ from that given in the structure
elucidation paper. In addition the CD spectrum (Fig. 2) in
the range from 300 to 450 nm00was also different and from
this it was concluded that t0h0 e 3 S,400S-configured compound
was in fact epi,epi-(300S,4 S)-polycephalin C and that the
isolated natural product had the R,R configuration about the
ring junction.
2.3. Synthesis of 300S,400S-1
Initial attempts at union of the two fragments bis-iodide 3
and dienoyltetramic acid 2 utilised the palladium catalyst
bis-(trifurylphosphine)palladium dichloride which had been
utilised to great success in our syntheses of erythroskyrine4b
and physarorubinic acid.4a Disappointingly, utilising this
catalyst did not lead to the desired double Stille coupling but
gave the homo-coupled polyenoyl-bis-tetramic acid 19 as
the major product, with only small amounts of the desired
double Stille product 20 being isolated. Following opti-
misation studies the double Stille product 20 could be
isolated in a good 53% yield utilising palladium bis(aceto-
nitrile) dichloride as the catalyst after size exclusion
chromatography (Scheme 8). The final step of the synthesis
removal of the TBS ethers was carried out with trifluoro-
acetic acid (TFA)/water (9:1) which facilitated smooth
deprotection when added and immediately removed under
reduced pressure (three 00tim0e0 s). Purification by reverse-
phase HPLC then gave (3 S,4 S)-1 in 64% yield and overall
3.3% yield from dimenthyl fumarate (Scheme 8).
To prove that this was correct the synthesis was repeated
starting from (2)-dime0n0 thyl fumarate to create the opposite
configuration at the 3 ,400 ring junction. As the reaction
sequence for preparation of the bis-iodide 3 had already
been elaborated synthesis of the bis-iodide 21 proceeded
uneventfully. Following Stille coupling with stannane 2,
deprotection with TFA/H2O gave polycephalin C 1 with
300R,400R stereochemistry at the ring junction (Scheme 9).
The spectroscopic data (1H and 13C NMR, MS, IR) of this
synthetic material were again in excellent agreement with
that published in the literature. However, and importantly,
in this case the optical rotation and CD spectrum (Fig. 3),
crucial for confirmation of configuration, were also in
excellent agreement with the published data.
The spectroscopic data (1H and 13C NMR, MS, IR) of this
Thus, the total synthesis of this unusual bistetramic acid,
polycephalin C 1 has been completed in a short and efficient
fashion and the goal of defining the absolute stereo-
chemistry of the ring junction achieved.
3. Experimental
3.1. General
All reactions were carried out under an atmosphere of argon,
and those not involving aqueous reagents were carried out in
oven-dried glassware, cooled under vacuum. Diethyl ether
(Et2O) and tetrahydrofuran were distilled over sodium
benzophenone ketyl; dichloromethane, methanol and
toluene were distilled over calcium hydride; pentane was
distilled over sodium and triethylamine from potassium
hydroxide. All other reagents and solvents were used as
supplied. Aqueous solutions are saturated unless otherwise
specified. Phosphate buffer refers to potassium dihydrogen
phosphate and sodium hydroxide in distilled water. Petrol
refers to petroleum ether bp 40–608C, which was distilled
prior to use and ether (Et2O) refers to diethyl ether.
Scheme 9. Reagents and conditions: (a) 5 mol% [Pd(MeCN)2Cl2], DMF,
room temperature, 1 h, 56%, (b) TFA/H2O (9:1)£3, room temperature,
74%.

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D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
Flash column chromatography was carried out using Merck
Kieselgel (230–400 mesh) under pressure unless otherwise
indicated. Analytical thin layer chromatography (TLC) was
performed using precoated glass-backed plates (Merck
Kieselgel 60 F254) and visualised by ultra-violet irradiation
(254 nm) or by staining with aqueous acidic ammonium
molybdate(IV) or potassium permanganate solutions as
appropriate.
(10 cm, 2.12 cm F, 5 mm). Method: Eluent A: water, 0.1%
TFA. B: acetonitrile 95%, water 5%, TFA 0.05%. Method:
3:1 A/B to 19:1 B/A over 35 min, flowrate 6 ml min21
detection at 254 nm.
,
3.1.1. (20S,2Z,4E,6E)-30-(tert-Butyldimethylsilyloxy)-20-
[(3-hydroxy-7-tri-n-butylstannylhepta-2,4,6-trienoyl)-
methylamino]-propionic acid methyl ester 8
1H NMR spectra were recorded in CDCl3 (unless otherwise
stated) on Bruker DPX-400, Bruker DRX-500 or Bruker
DRX-600 spectrometers and are reported as follows:
chemical shift, dH (in parts per million, ppm), (number of
protons, multiplicity, coupling constant, J, in Hertz, and
assignment). For spectra recorded in CDCl3, residual protic
solvent CHCl3 (dH¼7.26 ppm) was used as an internal
reference. 13C NMR spectra were recorded on the same
spectrometers at 100 or 125 or 150 MHz, using the central
resonance of CDCl3 (dC¼77.0 ppm) as the internal
reference unless otherwise stated.
Amino ester 5 (260 mg, 1.05 mmol) in THF (4 ml) was
added to thioester 4 (500 mg, 1.0 mmol) in THF (1.0 ml).
Triethylamine (700 ml, 5.0 mmol) was then added and the
reaction mixture cooled to 08C. Silver trifluoroacetate
(270 mg, 1.22 mmol) was then added in one portion and
the reaction mixture stirred at 08C for 20 min. Petrol (3 ml)
was then added and the reaction mixture filtered through a
pad of celite (£2, washing with petrol/ether 10:1). The
solvent was then removed under reduced pressure and the
residue immediately purified by flash column chromato-
graphy (petrol/ether 10:1 then 3:1] affording 8 (528 mg,
81%) as a yellow oil, RF 0.58 [petrol/ether 1:1];
DEPT-135 and two-dimensional (COSY, HMQC, HMBC)
NMR spectroscopy were used where appropriate, to aid in
[a]2D5¼215.6 (c 0.16, CH2Cl2); nmax (CH2Cl2, cm21
)
2952, 2928, 2856 (CH), 1745, 1632, 1591 (CvO, CvC);
dH (600 MHz, CDCl3) (k/e 25:75, major rotamer assigned)
7.15 (1H-k, dd, J¼15.5, 10.3 Hz, H-5), 7.00–6.93 (1H-k,
1H-e, m, H-6 (k), H-5 (e)), 6.70–6.58 (1H-k, 2H-e, m, H-7
(k), H-7, H-6 (e)), 6.20 (1H-k, d, J¼15.3 Hz, H-4), 5.88
(1H-e, d, J¼15.2 Hz,0H-4), 5.27 (1H-e, s, H-2), 5.11 (1H-e,
app q, J¼3.5 Hz, H-2 ), 5.07 (1H0-k, app q, J¼3.5 Hz, H-20),
4.16–4.11 (1H-k, 1H-e, m, Ha-3 ), 4.01–3.97 (1H-k, 1H-e,
m, Hb-30), 3.73 (3H-e, s, OCH3), 3.72 (3H-k, s, OCH3), 3.70
(2H-k, s, H-2), 3.13 (3H-k, s, NCH3), 3.11 (3H-e, s, NCH3),
1.59–1.43 (6H-k, 6H-e, m, CH2-2 Bu3Sn), 1.31 (6H-k, 6H-
e, app sextet, J¼7.4 Hz, CH2-3 Bu3Sn), 0.94 (6H-k, 6H-e,
app q, J¼9.0, 7.9, 8.4 Hz, CH2-1 Bu3Sn), 0.89 (9H-k, 9H-e,
t, J¼7.3 Hz, CH3 Bu3Sn), 0.86 (9H-k, 9H-e, s, SiC(CH3)3),
[0.05 (s, 6H-k, 6H-e) and 0.04 (6H-k, 6H-e), Si(CH3)2]; dC
(150 MHz, CDCl3) 193.7, 172.5, 170.0, 169.8, 169.6, 167.9
(k/e, C-3, C-1, C-10), 150.6 (e, C-5), 145.9 (k, C-5), 145.3,
144.6, 142.8 (1C-k, 2C-e, C-7, C-6 (e), C-7 (k)), 138.3 (k,
C-6), 127.0 (k, C-4), 125.2 (e, C-4), 89.5 (e, C-2), 62.0, 61.8
(k/e, C-30), 59.4 (k, C-20), 58.6 (e, C-20), 52.0 (k/e, OCH3),
48.0 (k, C-2), 34.6 (k, NCH3), 33.9 (e, NCH3), 29.1, 29.0
(k/e, CH2-2 Bu3Sn), 27.4, 27.2 (k/e, CH2-3 Bu3Sn), 25.7,
25.6 (k/e, SiC(CH3)3), 18.0 (k/e, SiC(CH3)3), 13.6 (k/e, CH3
Bu3Sn), 9.7, 9.6 (k/e, CH2-1 Bu3Sn), 25.6, 25.7, 25.8 (k/e,
Si(CH3)2); m/z (ESI) (Found: [MþNa]þ, 682.2926. C30H57-
NO5SiSn requires [MþNa]þ, 682.2903).
1
the assignment of signals in the H and 13C NMR spectra.
Where coincident coupling constants have been observed in
the NMR spectrum, the apparent multiplicity of the proton
resonance concerned has been reported.
Some compounds exist as a mixture of keto and enol
tautomers, abbreviated as k and e, respectively.
Mass spectra and accurate mass data were obtained on a
Micromass Platform LC–MS, Kratos MS890MS or Bruker
BIOAPEX 4.7 T FTICR spectrometer by electrospray
ionisation (ESI), electron impact (EI), chemical ionisation
(CI) or fast atom/ion bombardment (FAB) techniques at the
Department of Chemistry, Lensfield Road, Cambridge
and are reported as follows: signal (relative intensity,
assignment).
Optical rotations were measured on an Optical Activity
AA-1000 Polarimeter or a Perkin Elmer 343 Polarimeter
and [a]D values are reported in 1021 deg cm2 g21; concen-
tration (c) is in g 100 ml21
.
Infra-red spectra were recorded either as solutions (CH2-
Cl2/MeOH) or a KBr disk on a Perkin Elmer 1600 FTIR
spectrometer; alternatively as a film on a Perkin Elmer
Spectrum One FT-IR spectrometer.
3.1.2. (20S,2Z,4E)-30-(tert-Butyldimethylsilyloxy)-20-[(3-
hydroxyhepta-2,4,6-trienoyl)-methylamino]-propionic
acid methyl ester 9
Melting points were measured on a Reichert hot stage
apparatus, and are uncorrected. Microanalyses were per-
formed using a CE-440 Elemental Analyser in the
microanalytical laboratories at the Department of
Chemistry, Lensfield Road, Cambridge.
Thioester 4 (200 mg, 0.4 mmol) was dissolved in THF
(3 ml) and amino ester 5 (297 mg, 1.2 mmol) was added as a
solution in THF (2 ml). Triethylamine (139 ml, 1.0 mmol)
was then added and the reaction mixture cooled to 08C.
Silver trifluoroacetate (177 mg, 0.8 mmol) was then added
in one portion and the reaction stirred for 2 h at 08C. The
reaction mixture was filtered through a florisil pad [ether/
petrol 2:1] and the solvent removed under reduced pressure.
Flash column chromatography on florisil [petrol/ether 2:1 to
1:2] afforded 9 (61 mg, 45%) as a colourless oil, RF 0.41
CD spectra were recorded on a Jasco-810 spectro-
polarimeter themostated at 208C using 0.1 cm cuvettes.
Samples were dissolved in methanol and spectra were
subtracted by the appropriate background.
Preparative HPLC was carried out on a Gilson Autoprep
system using a Supelco, Supelcosile ABZþPLUS column

D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
6961
[petrol/ether 1:1]; dH (600 MHz, CDCl3) (k/e 20:80, major
rotamer assigned) 7.30–7.20 (1H-k, m, H-5), 7.02 (1H-e,
dd, J¼15.1, 11.0 Hz, H-5), [6.49–6.25 (2H-k, 1H-e, m),
5.94 (1H-e, d, J¼15.2 Hz), 5.67 (1H-k, d, J¼16.9 Hz), 5.55
(1H-k, d, J¼10.0 Hz), 5.45 (1H-e, d, J¼16.9 Hz) and 5.32
(1H-e, d, J¼10.1 Hz), H-4, H-6, Ha-7, Hb-7], 5.30 (1H-e, s,
H-2), 5.09 (1H-e, q, J¼3.5 Hz, H-20), 5.04 (1H-k, q,
J¼3.5 Hz, H-20), 4.14–4.08 (1H-k, 1H-e, m, Ha-30), 4.01–
3.91 (1H-k, 1H-e, m, Hb-30), 3.70 (3H-k, 3H-e, s, OCH3),
3.69 (2H-k, s, H-2), 3.11 (3H-k, s, NCH3), 3.09 (3H-e, s,
NCH3), 0.84 (9H-k, 9H-e, SiC(CH3)3), 0.03 (6H-k, 6H-e,
Si(CH3)2),; dC (150 MHz, CDCl3) 193.5, 172.9, 170.3,
169.9, 169.6, 168.1 (k/e, C-3, C-1, C-10), 144.7, 136.7,
136.1, 135.5, 129.6, 127.6 (k/e, C-4, C-5, C-6), 122.7 (k/e
C-7), 90.1 (e, C-2), 62.4, 62.1 (k/e, C-30), 59.8, 59.1 (k/e,
C-20), 52.4 (k/e, OCH3), 48.4 (k, C-2), 35.0, 34.3 (k/e,
NCH3), 26.1 (k/e, SiC(CH3)3), 18.4 (k/e, SiC(CH3)3), 25.2,
25.3 (k/e, Si(CH3)2).
passed through a pad of silica [petrol to 1% ether in petrol]
which afforded maleate 22 (36.0 g, 90%) as a white
amorphous solid, RF 0.43 [petrol/ether 20:1];
[a]2D5¼þ102.5 (c 0.12, CH2Cl2); (Found: C, 73.50; H,
10.30%. C24H40O4 requires C, 73.43; H, 10.27%); mp 78–
818C; nmax (CH2Cl2, cm21) 2954, 2927, 2865 (CH), 1729,
1711 (CvO); dH (600 MHz, CDCl3) 6.18 (2H, s, CHvCH),
4.79 (2H, td, J¼10.9, 4.3 Hz, H-10, H-100), 2.12–2.10 (2H,
m, Ha-60, Ha-600), 1.90 (2H, sept d, J¼6.9, 2.4 Hz,
0
0
00
00
CH3 CH0CH3 , CH3 CH00CH3 ), 1.70–1.68 (4H, m, Ha-30,
Ha-300, Ha-40, Ha-400), 1.53–1.47 (2H, m, H-50, H-500), 1.47–
1.38 (2H, m, H-20, H-200), 1.10–0.98 (4H, m, Hb-30, Hb-300,
Hb-60, Hb-600), [0.92 (6H, d, J¼6.5 Hz) and 0.89 (6H,
0
00
0
0
d, J¼7.0 Hz), CH0CH3 , CH00CH3 , CH3 CH0CH3 ,
00
00
CH3 CH00CH3 ], 0.92–0.84 (2H, m, Hb-40, Hb-4000)0 , 0.78
(6H, J¼6.9 Hz, CH3 CH0CH3 , CH3 CH00CH3 ); dC
(150 MHz, CDCl3) 164.7 (CvO), 129.8 (HCvCH), 75.3
(C-10, C-100), 47.0 (C-20, C-200), 40.6 (C-60,0C-6000), 34.3 (C-400,0
0
0
00
C-400), 31.4 (C-50, C-500), 26.1 (CH3 CH CH3 , CH3
0
3.1.3. (3Z,5S,20E,40E)-5-(tert-Butyl-dimethyl-silyloxy-
methyl)-3-(10-hydroxy-50-tri-n-butyl-stannyl-penta-20,40-
dienylene)-N-methyl-pyrrolidine-2,4-dione 2
00 0 0
CH00CH3 ), 23.4 (C-30, C-300), 22.0, 20.8 (CH3 CH0CH3 ,
CH3 CH0000CH3 , CH0CH3 , CH00CH3 ), 16.3 (CH3 CH0CH3 ,
00
00
00
00
0
00
0
0
CH3 CH CH3 ); m/z (ESI) (Found: [MþNa]þ, 415.2824.
C24H40O4 requires [MþNa]þ, 415.2829).
Freshly prepared sodium methoxide in methanol (8.0 ml,
4.0 mmol, 0.5 M) was added rapidly to a stirred solution of 8
(528 mg, 0.80 mmol) in methanol (10 ml) at 258C. After
2 min, saturated aqueous NH4Cl (5 ml) and ether (5 ml)
were added and the aqueous layer separated. The aqueous
layer was extracted into ether (2£5 ml) and the combined
organic phase was decanted to remove water prior to
removal of the solvent under reduced pressure, affording
tetramic acid 2 (13 mg, 90%) as a dark yellow oil,
3.1.5. (2E,10S,20R,50S)-But-2-enedioic acid bis-(20-iso-
propyl-50-methyl-cyclohexyl) ester 107
Morpholine (1.33 g, 15.3 mmol) in toluene (20 ml) was
added to a solution of di-(þ)-menthyl maleate 22 (45 g,
153 mmol) in toluene (180 ml) and the solution was heated
at 1008C for 10 h. The solution was cooled and diluted with
ether (200 ml). It was then washed sequentially with 3N HCl
(150 ml), saturated aqueous NaHCO3 (150 ml), water
(150 ml), and brine (150 ml). The organic phase was dried
(MgSO4) and the solvent removed under reduced pressure.
The resulting oil was passed through a pad of silica [petrol/
ether 20:1] and afforded fumarate 10 (36.6 g, 81%) as a
white crystalline solid, RF 0.54 [petrol/ether 20:1];
[a]2D5¼þ102.0 (c 0.15, CH2Cl2); (Found: C, 73.54; H,
10.36%. C24H40O4 requires C, 73.43; H, 10.27%) mp 52–
548C; nmax (CH2Cl2, cm21) 2955, 2870 (CH), 1718 (CvO);
dH (600 MHz, CDCl3) 6.82 (2H, s, CHvCH), 4.79 (2H, td,
J¼10.9, 4.4 Hz, H-10, H-100), 2.02 (2H, d, J¼11.9 Hz, Ha-60,
[a]2D5¼2116.4 (c 0.14, CH2Cl2); nmax (CH2Cl2, cm21
)
2956, 2928, 2855 (CH), 1706, 1623, 1587, 1541 (CvO,
CvC); dH (600 MHz, CDCl3) (major tautomer assigned)
7.32 (1H, dd, J¼15.2, 10.5 Hz, H-30), 7.06 (1H, d,
J¼15.2 Hz, H-20), 6.99 (1H, 0 d, J¼18.6 Hz, H-50), 6.83
(1H, dd, J¼18.6, 10.4 Hz, H-4 ), 3.98–3.93 (2H, m, Ha-100,
Hb-100), 3.68 (1H, app s, H-5), 3.04 (3H, s, NCH3), 1.55–
1.47 (6H, m, CH2-2 Bu3Sn), 1.35–1.29 (6H, m, CH2-3
Bu3Sn), 0.96 (6H, t, J¼8.0 Hz, CH2-1 Bu3Sn), 0.90 (9H, t,
J¼7.3 Hz, CH3 Bu3Sn), 0.82 (9H, s, SiC(CH3)3), [0.04 (3H,
s) and 0.01 (3H, s), Si(CH3)2]; dC (150 MHz, CDCl3) 192.6,
174.1, 1730.1 (C-4, C-2, C-10), 151.0 (C-50), 145.29, 145.26
(C-3000, C-4 ), 120.2 (C-20), 101.4 (C-3), 68.6 (C-5), 60.8
(C-1 ), 29.0 (CH2-2 Bu3Sn), 27.2 (CH2-3 Bu3Sn), 26.9
(NCH3), 25.6 (SiC(CH3)3), 17.95 (SiC(CH3)3), 13.6 (CH3
Bu3Sn), 9.7 (CH2-1 Bu3Sn), 25.7 (Si(CH3)2); m/z (ESI)
(Found: [MþNa]þ, 650.2664. C29H53NO4SiSn requires
[MþNa]þ, 650.2664).
0
0
Ha-600), 1.87 (2H, septd, J¼6.9, 2.6 Hz, CH3 CH0CH3 ,
CH3 CH00CH3 ), 1.71–1.68 (4H, m, Ha-30, Ha-300, Ha-40, Ha-
400),010 .53–1.48 (2H, m, H-50, H-500), 1.46–1.41 (2H, 0m0 , H-20,
H-2 ), 1.11–0.98 (4H, m, Hb-30, Hb-300, Hb-60, Hb-6 ), [0.91
00
00
(6H, d, J¼6.8 Hz) and 0.90 (6H, d, J¼7.1 Hz), CH0CH3 ,
0
CH00CH3 , CH3 CH0CH3 , CH3 CH00CH3 ], 0.91–0.89 (2H,
00
0
0
00
00
0
0
m, Hb-40, Hb-400), 0.76 (6H, d, J¼7.0 Hz, CH3 CH0CH3 ,
CH3 CH00CH3 ); dC (150 MHz, CDCl3) 164.6 (CvO),
133.8 (HCvC0H0 ), 75.3 (C-10, C-100), 47.0 (C-20,00 C-200),
40.7 (C-60, C-6 ), 34.2 (C-40, C-400), 31.4 (C-50, C-5 ), 26.3
00
00
3.1.4. (2Z,10S,20R,50S)-But-2-enedioic acid bis-(20-iso-
propyl-50-methyl-cyclohexyl) ester 227
(CH3 CH0CH3 , CH3 CH0000CH3 ), 23.4 (C-30,0 C-300) 22.0,
0 0 00 00
20.7 (CH3 CH0CH3 , CH3 CH00CH3 , CH0CH3 , CH00CH3 ),
0
0
00
00
Maleic anhydride (10.0 g, 102 mmol), (þ)-menthol (31.2 g,
200 mmol) and p-toluenesulfonic acid hydrate (0.58 g,
6.12 mmol) were dissolved in toluene (120 ml). The flask
was fitted with a Dean–Stark head and the reaction heated at
reflux for 17 h. The solution was allowed to cool and was
then washed with saturated aqueous NaHCO3 (100 ml). The
organic portion was washed further with water (100 ml) and
brine (100 ml), dried (MgSO4), filtered and the solvent
removed under reduced pressure. The pink residue was
16.3 (CH3 CH0CH3 , CH3 CH00CH3 ); m/z (ESI) (Found:
[MþNa]þ, 415.2824. C24H40O4 requires [MþNa]þ,
415.2829).
0
0
00
00
3.1.6. (1R,2R,10S,20R,50S)-Cyclohex-4-ene-1,2-dicarboxylic
acid bis-(20-isopropyl-50-methyl-cyclohexyl) ester 76c
Diethylaluminium chloride (140 ml, 140 mmol, 1.0 M in

6962
D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
hexanes) was added to a stirred solution of (þ)-dimenthyl-
fumarate 10 (27.5 g, 70 mmol) in dry toluene (400 ml) at
2608C. The deep red solution was stirred for 40 min, at
which point, butadiene (24 ml, 280 mmol) was condensed
separately and transferred via cannula to the reaction
mixture. After 36 h at 2608C the reaction mixture was
allowed to warm to 2108C, at which point water (250 ml)
was added in small portions (NOTE: CAUTION
REQUIRED) until the colour of the solution was dis-
charged. Once warmed to room temperature, the solution
was allowed to stand for 4 h in order to allow as much
butadiene polymerisation to occur as possible. Filtration
through celite was then carried out to remove polymeric
material. The aqueous layer was then extracted into ether
(2£200 ml) and the combined organic extracts were washed
sequentially with 3N HCl (300 ml), water (300 ml) and
brine (300 ml). The organic layer was then dried (MgSO4)
and the solvent was removed under reduced pressure. The
residue was left under vacuum until a gel formed, at which
point ether (200 ml) was added and the gel filtered through
celite to remove the remaining polymeric material. The
solvent was removed in vacuo and the residue passed
through a short pad of silica [petrol/ether 20:1], affording
the Diels–Alder adduct 7 (22.92 g, 73%) as a white
crystalline solid, RF 0.32 [petrol/ether 20:1]; [a]2D5¼þ25.7
(c 0.18, CH2Cl2); (Found: C, 75.29; H, 10.33%. C28H46O4
requires C, 75.29; H, 10.38%); mp 42–448C; nmax (CH2Cl2,
cm21) 2954, 2869 (CH), 1728 (CvO); dH (600 MHz,
CDCl3) 5.70–5.65 (2H, m, H-4, H-5), 4.66 (2H, td, J¼10.9,
4.3 Hz, H-10, H-100), 2.89–2.84 (2H, m, H-1, H-2), 2.43–
2.40 (2H, m, Ha-3, Ha-6), 2.18–2.14 (2H, m, Hb-3, Hb-6),
2.01–1.98 (2H, m, Ha-60, Ha-600), 1.87 (2H, septd, J¼6.9,
(CvO); dH (600 MHz, CDCl3) 7.52–7.49 (2H, m, 2£m-
CH), 7.26–7.21 (3H, m, 2£o-CH, p-CH), 4.64–4.56 (2H,
m, H-10, H-100), 4.40 (1H, app d, J¼2.8 Hz, H-4), 3.65 (1H,
app d, J¼2.5 Hz, H-5), 3.09 (1H, td, J¼11.5, 3.7 Hz, H-1),
2.93 (1H, app td, J¼12.0, 11.1, 3.7 Hz, H-2), 2.40–2.29
(2H, m, Ha-3, Ha-6), 2.17–2.06 (2H, m, Ha-60, Ha-600), 1.94–
0
0
1.9000(2H, m, Hb-3, Hb-6), 1.81–1.68 (2H, m, CH3 CH0CH3 ,
00
CH3 CH00CH3 ), 1.60 (4H, app d, J¼11.8 Hz, Ha-30, Ha-300,
Ha-40, Ha-400), 1.46–1.30 (4H, m, H-20, H-200, H-50, H-500),
1.01–0.75 (18H, m, Hb-30, Hb-0300, Hb-400, Hb-4000,0 Hb-60, Hb-
0
00
00
600, CH0CH3 , CH00CH3 , CH3 CH0CH3 , CH3 CH00CH3 ),
[0.67 (3H, d, J¼7.0 Hz) and 0.64 (3H, d, J¼7.0 Hz),
0
0
00
00
CH3 CH0CH3 , CH3 CH00CH3 ]; dC (150 MHz, CDCl3)
171.6, 171.5 (CvO), 132.9 (m-CH), 127.7, 126.500(p-CH,
2£o-CH), 125.9 (ipso-CSe), 72.9, 72.8 (C-10, C-1 ), 57.7
(C-4), 45.10, 45.06 (C-20, C-200), 44.2 (C-5), 39.00, 38.88,
38.85 (C-2, C-60, C-600), 3070 .5 (C-1), 32.5, 32.4 (C-30, C-300),
30.10(0 C-6), 29.6 (C-50, C-5 ), 26.8 (C-3), 24.2 (CH3 CH0CH3 ,
0
0
CH3 CH00CH3 ), 21.3 (C-40, C-400), 20.2, 0 19.08, 19.07
00
(CH3 CH0CH3 , CH3 CH00CH3 , CH0CH3 ,00 CH00CH3 ),
0
0
00
00
00
14.13, 14.08 (CH3 CH0CH3 , CH3 CH00CH3 ); m/z (ES)
0
0
00
661 (98, [MþNa]þ), 639 (100, [MþH]þ).
3.1.8. (1R,2R,4R,5R,10S,20R,50S)-4-Hydroxy-5-phenyl-
selanyl-cyclohexane-1,2-dicarboxylic acid bis-(20-iso-
propyl-50-methyl-cyclohexyl) ester 12
Water (37 ml, 2.05 mol) was added slowly to a stirred
solution of Diels–Alder adduct 7 (7.5 g, 15.7 mmol) in
acetonitrile (500 ml). Phenylselenium bromide (5.0 g,
21.2 mmol) was then added portionwise and the solution
heated at 508C for 12 h. Saturated aqueous NaHCO3
(400 ml) was added and the aqueous layer extracted into
ether (3£150 ml). The combined organic phase was
sequentially washed with saturated aqueous NaHCO3
(500 ml), water (500 ml) and brine (500 ml). It was then
dried (MgSO4), filtered and the solvent removed under
reduced pressure. Flash column chromatography [petrol/
ether 9:1 to 1:1] and trituration of the resulting yellow solid
furnished alcohol 12 (6.4 g, 75%) as a white amorphous
solid, RF 0.48 [petrol/ether 1:1]; [a]2D5¼þ30.2 (c 0.22,
CH2Cl2); (Found: C, 65.96; H, 8.49%. C34H52O5Se requires
0
0
00
00
2.7 Hz, CH3 CH0CH3 , CH3 CH00CH3 ), 1.69–1.65 (4H, m
Ha-30, Ha-300, Ha-40, Ha-400), 1.52–1.43 (2H, m, H-50, H-500),
1.42–1.37 (2H, m, H-20, H-200), 1.08–0.98 (4H, m, Hb-30,
Hb-300, Hb-60, Hb-600), [0.90 (6H, d, J¼6.8 Hz) and 0.89 (6H,
0
00
0
0
00
d, J¼7.1 Hz), CH0CH3 , CH00CH3 , CH3 CH0CH3 , CH3
00
CH00CH3 ], 0.95–0.84 (2H, m,00Hb-40, Hb-400), 0.73 (6H, d,
J¼6.9 Hz, CH3 CH0CH3 , CH3 CH00CH3 ); dC (150 MHz,
CDCl3) 174.9 (CvO), 125.4 (C-4, C-5), 74.7 (C-10, C-100),
47.40 (C-20,00C-200), 41.6 (C-1, C-2), 41.1 (C-60, C-600), 34.7
(C-4 , C-4 ), 0 31.8 (C-5000, C-500), 28.3 (C-3, C-060 ), 26.4
0
0
00
(CH3 CH0CH3 , CH3 CH 00CH3 ), 23.6 (C-30, 0 C-3 ), 22.4,
C, 65.89; H, 8.46%); mp 130–1318C; nmax (CH2Cl2, cm21
)
0
00
00
21.3 (CH3 CH0CH3 , CH3 CH00CH3 , CH0CH3 , CH00CH3 ),
3650–3300 (br, OH), 2955, 2926, 2870 (CH), 1727 (CvO);
dH (600 MHz, CDCl3) 7.58–7.57 (2H, m, 2£m-CH), 7.32–
7.26 (3H, m, p-CH, 2£o-CH), [4.67 (1H, td, J¼10.9, 4.4 Hz)
and 4.62 (1H, td, J¼10.9, 4.3 Hz), H-10, H-100], 3.77 (1H, br
s, H-4), 3.26–3.23 (1H, m, H-5), 3.18 (1H, dd, J¼11.6,
6.4 Hz, H-1), 3.06 (1H, dd, J¼11.2, 6.6 Hz, H-2), 2.46 (1H,
ddd, J¼14.1, 7.1, 4.1 Hz, Ha-3), 2.35–2.31 (2H, m, CHOH,
Ha-6), [2.00–1.97 (1H, m) and 1.94–1.88 (1H, m), Ha-60,
Ha-600], 1.94–1.88 (1H, m, Hb-3), 1.86–1.78 (3H, m, Hb-6,
0
0
00
00
16.4 (CH3 CH0CH3 , CH3 CH00CH3 ); m/z (ESI) (Found:
[MþNa]þ, 469.3294. C28H46O4 requires [MþNa]þ
469.3294).
0
0
00
00
3.1.7. (1R,2R,4R,5R,10S,20R,50S)-4-Chloro-5-phenyl-
selanyl-cyclohexane-1,2-dicarboxylic acid bis-(20-iso-
propyl-50-methyl-cyclohexyl) ester 11
0
0
00
00
Benzeneselenyl chloride (88 mg, 0.46 mmol) was added
portionwise to a stirred solution of Diels–Alder adduct 7
(200 mg, 0.42 mmol) in MeCN/H2O (14 ml, 13:1) at room
temperature. After 30 min, saturated aqueous NaHCO3
(20 ml) was added. The aqueous layer was removed and
re-extracted into CH2Cl2 (2£20 ml). The combined organic
phase was then washed with water (30 ml) and brine
(30 ml), dried (MgSO4) and the solvent removed under
reduced pressure affording chloride 11 as a yellow solid
which was characterised without further purification, RF 0.8
[CH2Cl2]; nmax (CH2Cl2, cm21) 2954, 2869 (CH), 1726
CH3 CH0CH3 , CH3 CH00CH3 ), 1.67–1.65 (4H, m, Ha-30,
Ha-300, Ha-40, Ha-400), 1.51–1.44 (2H, m, H-50, H-500), 1.41–
1.35 (2H, m, H-20, H-200), 1.07–0.084 (18H, m, Hb-30, Hb-300,
Hb-40,0H0 b-400, Hb-60, Hb-600, CH0CH3 , CH00CH3 , CH3 CH0CH3-
00
0
0, CH3 CH00CH3 ), [0.71 (3H, d, J¼7.2 Hz) and 0.70 (3H, d,
00
J¼7.2 Hz) CH3 CH0CH3 , CH3 CH00CH3 ]; dC (150 MHz,
CDCl3) 173.2, 173.1 (CvO), 135.3 (m-CH), 129.2, 128.1
(p-CH, 2£o-CH), 127.2 (ipso-CSe), 74.8, 74.7 (C-10, C-100),
68.7 (C-4), 47.4 (C-5), 040 6.90, 46.87 (C-20, C-200), 41.3 (C-2),
40.7, 40.6 (C-60, C-6 ), 40.4 (C-1), 34.23, 34.20 (C-30,
C-300), 31.6 (C-6), 31.4, 31.3 (C-50, C-500), 29.9 (C-3),
0
0
00
00

D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
00
6963
0
0
00
26.11, 26.09 (CH3 CH0CH3 , CH3 CH00CH3 ), 23.2, 23.1
75.63; H, 9.97%); mp 54–558C; nmax (CH2Cl2, cm21) 2953,
2930, 2869 (CH), 1729, 1702, (CvO), 1642 (CvC); dH
(600 MHz, CDCl3) 7.09–7.08 (1H, m, H-3), 6.11–6.06
(2H, m, H-4, H-5), 4.77–4.73 (1H, td, J¼10.9, 4.4 Hz,
H-10), 4.65–4.61 (1H, td, J¼10.9, 4.3 Hz, H-100), 3.66 (1H,
dd, J¼9.8, 2.6 Hz, H-1), 2.93–2.89 (1H, m, Ha-6), 2.52 (1H,
app dd, J¼18.6, 9.8 Hz, Hb-6), 2.09–2.07 (1H, m, Ha-60),
0
0
(C-40, C-400), 21.98, 21.97, 20.80, 20.77 (CH3 CH0CH3 ,
00
00
00
00
0
00
0
0
CH3 CH0000CH3 , CH0CH3 , CH00CH3 ), 16.0 (CH3 CH0CH3 ,
C34H52O5Se requires [MþNa]þ, 643.2853).
CH3 CH CH3 ); m/z (ESI) (Found: [MþNa]þ, 643.2878.
3.1.9. (1R,2R,3Z,5R,10S,20R,50S)-5-Hydroxy-cyclohex-3-
ene-1,2-dicarboxylic acid bis-(20-isopropyl-50-methyl-
cyclohexyl) ester 13
1.95–1.89 (2H, m, Ha-600, 00CH3 CH0CH3 ), 1.84 (1H, app
0
0
quintd, J¼7.0, 2.8 Hz, CH3 CH00CH3 ), 1.70–1.63 (4H, m,
00
Ha-30, Ha-300, Ha-40, Ha-400), 1.55–1.49 (1H, m, H-50),
1.48–1.42 (2H, m, H-5000, H-20), 1.35–1.30 (1H, m, H-2000),
1.12–1.05 (1H, m, Hb-3 ), 1.04–0.98 (2H, m, Hb-300, Hb-6 ),
A solution of m-CPBA (57%, 3.14 g, 10.4 mmol) in
dichloromethane (60 ml) was added dropwise to a stirred
solution of 12 (5.86 g, 9.45 mmol) in dichloromethane at
2308C. After 5 min, diisopropylamine (5.3 ml, 37.5 mmol)
was added and the reaction mixture was heated at 508C for
14 h. Saturated aqueous NaHCO3 (100 ml) was added and
the aqueous phase re-extracted into dichloromethane
(2£50 ml). The combined organic phase was washed with
saturated aqueous Na2S2O3 (150 ml), saturated aqueous
NaHCO3 (150 ml) and brine (150 ml), dried (MgSO4),
filtered and the solvent removed under reduced pressure.
Column chromatography [CH2Cl2 to 0.5% MeOH in
CH2Cl2] then furnished allylic alcohol 13 (4.01 g, 92%) as
a pale yellow oil, RF 0.5 [3% MeOH in CH2Cl2];
0.94–0.79 (150H, m, Hb-40, Hb-400, Hb-600, CH0CH3 ,
0
00
0
0
00
00
CH00CH3 , CH3 CH0CH3 , CH3 CH00CH3 ), 0.75 (3H, d,
0
00
J¼6.9 Hz, CH3 CH0CH3 ), 0.71 (3H, d, J¼6.9 Hz, CH3
00
CH00CH3 ); dC (150 MHz, CDCl3) 172.8, 166.6 (CvO),
133.3 (C-3), 131.8 (C-5), 126.8 (C-2), 124.2 (C-4), 750.2
(C-10), 74.8 (C-100), 47.6 (C-20), 47.40 (C-200), 41.4 (C-6 ),
41.00(C-600), 37.2 (C-1), 34.8, 34.7 (C-4 , C-400), 031.80, 31.76
(C-5 , C-500), 26.9 (C-6), 26.6, 26.2 (CH3 CH CH3 , CH3
0
0
00
00
CH00CH3 ), 230.4 (C-30), 23.1 (C-300), 22.44, 22.39, 21.3, 21.2
(CH3 CH0CH3 , CH3 CH00CH3 , CH0CH3 , CH00CH3 ), 16.8
0
00
00
0
00
(CH3 CH0CH3 ), 16.2 (CH3 CH00CH3 ); m/z (ESI) (Found:
[MþNa]þ 467.3137. C28H44O4 requires [MþNa]þ,
467.3140).
0
0
00
00
[a]2D5¼þ43.9 (c 0.1, CH2Cl2); nmax (CH2Cl2, cm21
)
3600–3100 (br, OH), 2955, 2869 (CH), 1728 (CvO); dH
(600 MHz, CDCl3) 5.26–5.91 (2H, m, H-3, H-4), [4.70 (1H,
td, J¼10.8, 4.3 Hz) and 4.69 (1H, td, J¼10.8, 4.3 Hz), H-10,
H-100], 4.23 (1H, br s, H-5), 3.48–3.46 (1H, m, H-2), 3.10
(1H, ddd, J¼12.5, 9.9, 3.3 Hz, H-1), 2.18–2.13 (1H, m, Ha-
6), 2.01–1.99 (2H,00m, Ha-600,0 Ha-600), 1.90–1.80 (3H, m,
3.1.11. (1R,2R,3Z,5R,10S,20R,50S)-5-Methanesulfonyloxy-
cyclohex-3-ene-1,2-dicarboxylic acid bis-(20-isopropyl-
50-methyl-cyclohexyl) ester 15
Triethylamine (9.67 ml, 69.4 mmol) was added to a solution
of allylic alcohol 13 (24.2 g, 52.2 mmol) in dichloro-
methane (240 ml) and the solution was cooled to 2788C.
Methanesulfonyl chloride (4.73 ml, 61.1 mmol) was added
and the solution allowed to warm to 2158C (Note: TLC
appears dirty due to decomposition of desired product on
silica). Saturated aqueous NaHCO3 (2 ml) was then added
and the organic layer separated. The aqueous layer was
further extracted into dichloromethane (2£200 ml) and the
combined organic phase washed with saturated aqueous
NaHCO3 (300 ml) and brine (300 ml). It was then dried
(MgSO4), filtered and the solvent removed under reduced
pressure giving crude mesylate 15 (25.7 g, 87%) as a pale
yellow solid. A small amount was triturated with petrol for
full characterisation, [a]2D5¼þ73.3 (c 0.09, CH2Cl2); mp
93–948C; nmax (CH2Cl2, cm21) 2955, 2870 (CH), 1729
(CvO), 1361, 1175 (SO2O); dH (600 MHz, CDCl3) 6.16
(1H, dd, J¼10.0, 2.4 Hz, H-3), 5.99–5.96 (1H, m, H-4),
5.19–5.18 (1H, m, H-5), 4.74–4.68 (2H, m, H-10, H-100),
3.51 (1H, d, J¼9.5 Hz, H-2), 3.17–3.13 (1H, m, H-1), 3.04
(3H, s, CHOSO2CH3), 2.42 (1H, d, J¼14.4 Hz, Ha-6),
2.00–1.98 (2H, m, Ha-60, Ha-600), 1.95–1.93 (1H, m, Hb-6),
CH3 CH0CH3 , CH3 CH00CH3 , Hb-6), 1.69–1.66 (5H, m,
Ha-30, Ha-300, Ha-40, Ha-400, CHOH), 1.55–1.48 (2H, m, H-50,
H-500), 1.440–0 1.40 (2H, m, H-20, H-200), 1.10–0.97 (4H, m,
Hb-30, Hb-3 , Hb-60, Hb-600), 0.91–0.76 (14H, m, Hb-40, Hb-
0
0
0
00
0
0
00
00
400, CH0CH3 , CH00CH3 , C0H3 CH0C0H3 , CH3 CH00CH3 ),
0.74 (6H, d, J¼7.0 Hz, CH3 CH0CH3 , CH3 CH00CH3 ); dC
(150 MHz, CDCl3) 174.5, 172.1 (CvO), 129.7, 128.2 (C-3,
C-4), 75.5, 75.1 (C-10, C-100),0 63.1 0(0C-5), 47.4 (C-20, C-200),
44.90(C-2), 41.20, 41.15 (C-6 , C-6 ), 37.5 (C-1), 34.7, 34.6
(C-4 , C-400), 33.5 (C-6), 31.82, 31.80 (C-50, C-500), 26.4
00
00
(CH3 CH0CH3 , CH3 CH00CH3 ), 23.5 00(C-30, C-300), 22.41,
0
0
00
00
22.39 (CH3 CH0CH3 , CH03 CH00CH3 ), 21.3 (CH0CH3 ,
0
0
00
0
CH00CH3 ), 16.4, 16.3 (CH3 CH0CH3 , CH3 CH00CH3 ); m/z
(ESI) (Found: [MþNa]þ, 485.3243. C28H46O5 requires
[MþNa]þ, 485.3259).
00
0
00
00
3.1.10. (1R,2E,4Z,10S,20R,50S)-Cyclohexa-2,4-diene-1,2-
dicarboxylic acid bis-(20-isopropyl-50-methyl-cyclohexyl)
ester 14
p-Toluenesulfonyl chloride (57 mg, 0.3 mmol) was added in
one portion to a stirred solution of allylic alcohol 13 (93 mg,
0.3 mmol) in pyridine (0.25 ml) at room temperature. The
reaction was heated at 408C for 6 h at which point the
reaction mixture was poured onto copper sulfate solution
(5 ml). It was then extracted into ether (3£5 ml) and washed
sequentially with copper sulfate (3£5 ml), water (5 ml) and
brine (5 ml). The organic phase was then dried (MgSO4),
filtered and the solvent removed under reduced pressure,
furnishing diene 14 (60 mg, 67%) as a white crystalline
solid, RF 0.35 [petrol/ether 10:1]; [a]2D5¼þ144.6 (c 0.09,
CH2Cl2); (Found: C, 75.40; H, 9.81%. C28H44O4 requires C,
1.84 (2H, app td, J¼6.7 Hz, 2.2, CH3 CH0CH3 , CH3
0
0
00
00
CH00CH3 ), 1.68 (4H, app d, J¼11.8 Hz, Ha-30, Ha-300, Ha-40,
Ha-400), 1.49–1.39 (4H, m, H-50, H-500, H-20, H-200), 1.07–
0.97 (4H, m, Hb-30, Hb-300, Hb-60, Hb-600), 0.91–0.89
0
00
0
0
(14H, m, Hb-40, Hb-400, CH0CH3 , CH00CH3 , CH3 CH0CH3 ,
00
00
0
0
00
CH3 CH0000CH3 ), 0.75–0.74 (6H, m, CH3 CH0CH3 , CH3
CH00CH3 ); dC (150 MHz, CDCl3) 173.4, 171.1 (CvO),
132.2 (C-3), 124.80(C-4), 75.8, 75.4 (C-10, C-100), 72.6 (C-5),
47.34, 47.29 (C-2 , C-200), 44.6 (C-2), 41.13, 41.12 (C-60,
C-600), 39.4 (CHOSO2CH3), 37.5 (C-1), 34.6 (C-40, C-400),
31.79, 31.77 (C-50, C-500), 31.5 (C-6), 26.5, 26.4 (CH3
0

6964
D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
0
00
00
CH0CH3 , CH3 CH00CH3 )0,0 23.5 (C-30, C-300),0 22.3, 21.22,
(3£40 ml) and pH 7 buffer (2£40 ml) before being dried
(Na2SO4), filtered and the solvent removed under reduced
pressure. This provided 1,4-dialdehyde 18 (215 mg, 87%) as
a pale yellow liquid, RF 0.28 [CH2Cl2]; [a]2D5¼240.0 (c
0.08, CH2Cl2); nmax (CH2Cl2, cm21) 2925, 2839, 2722
(CH), 1714 (CvO); dH (600 MHz, CDCl3) 9.74 (1H, s,
H-10), 9.67 (1H, s, H-20), 5.98–5.93 (1H, m, H-4), 5.83 (1H,
dd, J¼10.0, 1.6 Hz, H-3), 3.50–3.49 (1H, m, H-2), 2.99–
2.96 (1H, m, H-1), 2.12–2.06 (2H, m, Ha-5, Hb-5), 2.00–
1.95 (1H, m, Ha-6), 1.79–1.73 (1H, m, Hb-6); dC (150 MHz,
CDCl3) 201.9 (C-10), 199.1 (C-20), 130.6 (C-4), 119.6 (C-3),
48.2 (C-2), 45.1 (C-1), 23.2 (C-5), 20.3 (C-6); m/z (EI)
(Found: [M]þ, 138.0688. C8H10O2 requires [M]þ,
138.0681).
0
0
00
00
21.18 (CH3 CH0CH3 , CH3 CH00CH3 , CH0CH3 , CH00CH3 ),
16.3 (CH3 CH0CH3 , CH3 CH00CH3 ); m/z (ESI) (Found:
[MþNa]þ 563.3021. C29H48O7S requires [MþNa]þ,
563.3013).
0
0
00
00
3.1.12. (1R,2Z,6R)-(6-Hydroxymethyl-cyclohex-2-enyl)-
methanol 6
LiAlH4 (14.2 ml, 14.2 mmol, 1.0 M in THF) was added
dropwise to a stirred solution of mesylate 15 (1.0 g,
1.78 mmol) in THF (25 ml) at 2788C. The reaction mixture
was allowed to warm to room temperature overnight at
which point ethyl acetate (10 ml) was added dropwise.
Ground sodium sulfate decahydrate was then added
portionwise and the reaction mixture stirred for 10 h.
Filtration and evaporation gave a colourless oil (273 mg,
85%, SN2/SN20 5:1) and flash column chromatography
[EtOAc] afforded diol 6 (159 mg, 64%) as a pale brown oil,
RF 0.33 [ether/MeOH 19:1]; [a]2D5¼246.0 (c 0.15, CH2Cl2);
nmax (CH2Cl2, cm21) 3600–3100 (br, OH), 3019 (alkene
C–H), 2921, 2876 (CH); dH (600 MHz, CDCl3) 5.80 (1H,
ddd, J¼9.9, 6.2, 3.5 Hz, H-3), 5.45 (1H, dd, J¼9.9, 2.2 Hz,
H-2), 3.81 (2H, s, 2£OH), 3.66 (1H, dd, J¼10.8, 3.9 Hz,
Ha-10), 3.61 (1H, dd, J¼10.8, 4.6 Hz, Ha-20), 3.56 (1H, dd,
J¼10.8, 7.3 Hz, Hb-20), 3.49 (1H, dd, J¼10.8, 7.8 Hz, Hb-
10), 2.15 (1H, m, H-1), 2.06–2.02 (2H, m, Ha-4, Hb-4),
1.71–1.64 (2H, m, Ha-5, H-6), 1.40–1.33 (1H, m, Hb-5); dC
(150 MHz, CDCl3) 129.2 (C-3), 127.3 (C-2), 67.2 (C-20),
66.6 (C-10), 42.7 (C-1), 39.9 (C-6), 24.5 (C-5), 24.2 (C-4);
m/z (ESI) (Found: [MþNa]þ, 165.0894. C8H14O2 requires
[MþNa]þ, 165.0891).
3.1.15. (1Z,3R,4R,10E)-3,4-Bis-(20-iodo-vinyl)-cyclo-
hexene 3
A solution of dialdehyde 18 (100 mg, 0.72 mmol) and CHI3
(638 mg, 1.62 mmol) in THF (10 ml) was added to a rapidly
stirred slurry of CrCl2 (885 mg, 7.2 mmol) in THF (5 ml) at
08C. After 30 min, the ice bath was removed and the
reaction was allowed to warm to room temperature. After
2 h, ether (100 ml) and water (100 ml) were added. The
organic layer was separated and the aqueous further
extracted into ether (2£50 ml). The combined organic
phase was washed with saturated aqueous NaHCO3
(2£100 ml), saturated aqueous Na2S2O3 (1£100 ml), water
(2£100 ml) and brine (1£100 ml). This was then dried
(MgSO4), filtered and the solvent removed under reduced
pressure, providing divinyl iodide 3 (110 mg, 40%) as a pale
yellow oil, RF 0.35 [petrol]; nmax (CH2Cl2, cm21) 3021,
2920, 2854 (CH), 1650, 1601 (CvC); dH (600 MHz,
CDCl3) 6.48 (1H, dd, J¼14.4, 8.1 Hz, H-10), 6.40 (1H, dd,
J¼14.4, 8.1 Hz, H-100), 60.008 (1H, d, J¼14.4 Hz, H-20), 6.07
(1H, d, J¼14.4 Hz, H-2 ), 5.82–5.79 (1H, m, H-1), 5.48
(1H, dd, J¼7.9, 2.2 Hz, H-2), 2.67–2.64 (1H, m, H-3),
2.27–2.03 (3H, m, H-4, Ha-6, Hb-6), 1.80–1.76 (1H, m, Ha-
5), 1.53–1.43 (1H, m, Hb-5); dC (150 MHz, CDCl3) 148.6
(C-100), 147.9 (C-10), 128.6 (C-1), 126.4 (C-2), 76.6 (C-200),
75.5 (C-20), 46.9 (C-3), 45.2 (C-4), 26.1 (C-5), 23.7 (C-6);
m/z (ESI) 132 (100, [M–I2]þ).
3.1.13. (1R,3Z,6R)-(6-Hydroxymethyl-cyclohex-3-enyl)-
methanol 16
A small amount (20 mg) of diol 16 was isolated for full
characterisation, RF 0.39 [ether/MeOH 19:1]; [a]2D5¼269.0
(c 0.20, CH2Cl2); (Found: C, 67.56; H, 9.91%. C8H14O2
requires C, 67.57; H, 9.92%); nmax (CH2Cl2, cm21) 3600–
3050 (br, OH), 3024, 2890, 2801 (CH); dH (600 MHz,
CDCl3) 5.65 (2H, d, J¼5.7 Hz, H-3, H-4), [3.75–3.72 (2H,
m) and 3.62–3.58 (2H, m), Ha-10, Hb-10, Ha-20, Hb-20], 2.78
(2H, t, J¼5.5 Hz, 2£CH2OH), 2.04–2.01 (2H, m, Ha-2, Ha-
5), 1.90–1.85 (2H, m, Hb-2, Hb-5), 1.72–1.67 (2H, m, H-1,
H-6); dC (150 MHz, CDCl3) 126.0 (C-3, C-4), 66.3 (C-10,
C-20), 39.7 (C-1, C-6), 28.5 (C-2, C-5); m/z (ESI) (Found:
[MþNa]þ, 165.0884. C8H14O2 requires [MþNa]þ,
165.0891).
3.1.16.
(3Z,5S,20E,40E,60E,300S,400S,1000E,3000E,5000E,7000Z,50000S)-5-
tert-butyldimethylsilyloxymethyl-3-{70-{400-[7000-(50000-tert-
butyldimethylsilyloxymethyl-10000-methyl-20000,40000-dioxo-
pyrrolidin-30000-ylidene)-7000-hydroxy-hepta-1000,3000,5000-tri-
enyl]cyclohexen-300-yl}-10hydroxy-hepta-20,40,60-trien-10-
ylene}-1-methylpyrrolidine-2,4-dione 20. A solution of
bis-(acetonitrile) dichloropalladium (7.0 mg, 0.03 mmol) in
DMF (1 ml) was added to a stirred solution of divinyl iodide
3 (70 mg, 0.18 mmol) and stannane 2 (284 mg, 0.45 mmol)
in DMF (2 ml) at room temperature. The reaction was
stirred for 1 h at which point ethyl acetate (50 ml) and water
(50 ml) were added. The organic layer was separated,
washed with water (6£50 ml) and the solvent removed
under reduced pressure. Size exclusion chromatography on
Sephadex LH-20 [CH2Cl2/MeOH 1:1] then afforded 20
(77 mg, 53%) as an orange amorphous solid, RF 0.45 [3%
3.1.14. (1R,2R,3Z)-Cyclohex-3-ene-1,2-dicarbaldehyde
18
Oxalyl chloride (609 ml, 7.0 mmol) in CH2Cl2 (12.5 ml)
was cooled to 2788C and DMSO (1.24 ml, 17.5 mmol) in
CH2Cl2 (12.5 ml) was added via cannula. The reaction
mixture was stirred at 2788C for 1 h before a solution of the
diol 6 (250 mg, 1.75 mmol) in CH2Cl2 (12.5 ml) was added
dropwise via cannula. The reaction mixture was stirred for
30 min at which point DIPEA (2.42 ml, 14.0 mmol) was
added dropwise over 5 min. The reaction mixture was
stirred at 2788C for 15 min and then warmed to 08C. It was
stirred for 5 min at 08C and then washed with cold 1N HCl
MeOH in CH2Cl2]; mp 75–778C; nmax (CH2Cl2, cm21
)
3600–3100 (br, OH), 2929, 2857 (CH), 1701, 1611, 1598,
1556 (CvO, CvC); dH (600 MHz, CDCl3) 7.45 (2H, dd,

D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
6965
J¼15.0, 11.5 Hz, H-30, H-5000), 7.12 (2H, d, J¼0 15.0 Hz, H-20,
H-6000), 6.61 (2H, dd, J¼14.0, 11.3 Hz, H-5 , H-3000), [6.40
(1H, dd, J¼14.8, 11.5 Hz) and 6.39 (1H, dd, J¼14.6,
11.4 Hz), H-40, H-4000], 6.21 (1H, dd, J¼15.2, 10.3 Hz,
H-2000), 6.20 (1H, dd, J¼15.1, 10.6 Hz, H-60), 5.96 (1H, d0d,
J¼15.2, 7.9 Hz, H-1000), 5.87 (1H, dd, J¼15.1, 8.1 Hz, H-7 ),
5.83–5.81 (1H, m, H-100), 5.52 (1H, dd, J¼10.1, 1.8 Hz,
H-200), 3.96 (2H, dd, J¼10.9, 2.4 Hz, Ha-6, Ha-60000), 3.92
(2H, dd, J¼10.9, 3.9 Hz, Hb-6, Hb-60000), 3.67 (2H, m, H-5,
H-50000), 3.03 (6H, s, NCH3, NCH30000), 2.77 (1H, br s, H-300),
2.22 (1H, app dd, J¼15.6, 7.9 Hz, H-400), 2.09 (2H, br s, Ha-
600, Hb-600), 1.82–1.73 (1H, m, Ha-500), 1.62–1.41 (1H, m,
Hb-500), 0.80 (18H, s, SiC(CH3)3, SiC(CH30000)3), [0.03 (6H, s)
and 20.01 (6H, s) Si(CH3)2, Si(CH30000)2]; dC (150 MHz,
CDCl3) 192.47 (C-4, C-40000), 174.06 (C-2, C-20000), 172.24
(C-10, C-7000), 144.21, 144.15 (C-30, C-5000), 143.39 (C-70,
C-1000), 142.80, 142.60 (C-50, C-3000), 130.62 (C-6000), 129.99,
129.87, 129.83 (C-40, C-4000,0 C-2000), 128.22 (C-1 ), 127.56
(C-200), 120.96, 120.87000(0C-2 , C-6000), 100.84, 100.82 (C-3,
C-30000), 68.61 (C-5, C-5 ), 60.95 0(0C-6, C-60000), 44.51 (C-300),
43.07 (C-400), 27.06, 26.98 (C-5 , NCH3, NCH30000), 25.56
(SiC(CH3)3, SiC(CH30000)3), 24.02 (C-600), 17.95 (SiC(CH3)3,
SiC(CH30000)3), 25.66, 25.71 (Si(CH3)2, Si(CH30000)2); m/z
(ESI) (Found: [MþNa]þ, 827.4079. C44H64N2O8Si requires
[MþNa]þ, 827.4099).
MeOH/H2O 60:40:9]; [a]2D5¼2167.5 (c 0.0041, MeOH);
nmax (film, cm21) 3600–3050 (br, OH), 3021, 2930, 1685,
1636, 1595, 1553, 1482, 1446, 1408, 1357, 1287, 1254,
1134, 1007, 916; UV (c 3.63 mmol, MeOH), lmax (lge)/
nm21 276.0 (0.215), 365.0 (0.22); dH (600 MHz, CDCl3/
CD3OD 1:1, referenced to residual CH3OH) 7.47 (2H, dd,
J¼15.0, 11.5 Hz, H-30, H-5000), 7.10 (2H, d, J¼15.000H0 z, H-20,
H-6000), 6.66 (2H, 0dd, J¼00014.7, 10.9 Hz, H-50, H-3 ), 6.41–
6.35 (2H, m, H-4 , H-4 ), 6.24–6.18 (2H, m, H-60, H-2000),
5.98 (1H, dd, J¼15.3, 7.9 Hz, H-1000), 5.89 (1H, dd, J¼15.0,
8.1 Hz, H-70), 5.81–5.78 (1H, m, J¼2.2 Hz, H-100), 5.49
(1H, dd, J¼10.1, 2.1 Hz, H-200), 3.90 (4H, app s, Ha-6, Ha-
60000, Hb-6, Hb-60000), 3.69 (2H, s, H-5, H-50000), 3.02 (6H, s,
NCH3, NCH30000), 2.79–2.73 (1H, m, H-300), 2.23–2.18 (1H,
m, H-400), 2.07 (2H, br s, Ha-600, Hb-600), 1.81–1.78 (1H, m,
Ha-500), 1.56–1.48 (1H, m, Hb-500); dC (125 MHz, CDCl3/
CD3OD 1:1, referenced to residual CH3OH) 194.21 (C-4,
C-40000), 174.052 (C-2, C-20000), 173.02 (C-10, C-7000), 145.69,
145.64 (C-3 , C-5000), 145.48 (C-10000), 144.66 (C-70), 144.35
000
(C-3000), 144.13 (C-50), 131.32 (C-6 ), 130.58 (C-2 ), 130.36,
00
130.19 (C-4,0 C-4000), 128.74 (C-100), 128.03 (C-2 ), 120.98,
120.87 (C-2 , C-6000), 101.34 (C-3,00 C-30000), 69.29 (C-5,
C-50000), 59.13 (C-6, C-60000), 45.23 (C-3 ), 43.85 (C-400), 27.69
(C-500), 26.90 (NCH3, NCH30000), 24.41 (C-600); m/z (ESI)
(Found: [MþNa]þ, 599.2357. C32H36N2O8 requires
[MþNa]þ, 599.2369).
3.1.17. (3Z,5S,20E,40E,60E,80E,100Z,500S)-5-tert-butyl-
dimethylsilyloxymethyl-3-[100-(500-tert-butyldimethyl-
silyloxymethyl-100-methyl-200,400-dioxo-pyrrolidine-3-yli-
dene)-10,100-dihydroxydeca-20,40,60,80-tetraen-10-ylene]-
1-methylpyrrolidine-2,4-dione 19. A small amount of side
product 19 was isolated for characterisation purposes, RF
0.28 [3% MeOH in CH2Cl2]; nmax(CH2Cl2, cm21) 3600–
3000 (br, OH), 2928, 2857 (CH), 1701, 1611, 1541 (CvO,
CvC); dH(600 MHz, CDCl3) 7.48 (2H, dd, J¼15.1,
11.1 Hz, H-80, H-30), 7.25 (2H, d, J¼150.1 Hz, H-90, H-20),
6.74 (2H, m, J¼11.3 Hz, H-60, H-5 ), 6.68 (2H, m,
J¼11.3 Hz, H-70, H-40), 3.97 (2H, dd, J¼10.9, 2.8 Hz, Ha-
6, Ha-600), 3.95 (2H, dd, J¼10.9, 4.2 Hz, Hb-6, Hb-600), 3.68
3.1.19.
(3Z,5S,20E,40E,60E,300R,400R,1000E,3000E,5000E,7000Z,50000S)-5-
tert-butyldimethylsilyloxymethyl-3-{70-{400-[7000-(50000-tert-
butyldimethylsilyloxymethyl-10000-methyl-20000,40000-dioxo-
pyrrolidin-30000-ylidene)-7000-hydroxy-hepta-1000,3000,5000-tri-
enyl]cyclohexen-300-yl}-10hydroxy-hepta-20,40,60-trien-10-
ylene}-1-methylpyrrolidine-2,4-dione 23. A solution of
bis-(acetonitrile) dichloropalladium (0.84 mg, 3.2 mmol) in
DMF (0.5 ml) was added to a stirred solution of divinyl
iodide 21 (25.6 mg, 0.066 mmol) and stannane 2 (106 mg,
0.169 mmol) in DMF (2.5 ml) at room temperature. The
reaction was stirred for two h at which point ethyl acetate
(50 ml) and water (50 ml) were added. The organic layer
was separated, washed with water (4£50 ml) and the solvent
removed under reduced pressure. Size exclusion chroma-
tography on Sephadex LH-20 [CH2Cl2/MeOH 1:1] then
afforded 23 (29.7 mg, 56%) as an orange amorphous solid,
mp 89–918C (dec.); [a]2D5¼2140 (c 0.05, CHCl3); nmax
(film, cm21) 3100–2390 (br, OH), 2927, 2856 (CH), 1701,
1596, 1555 (CvO, CvC); dH (600 MHz, CDCl3) 7.45 (2H,
dd, J¼14.8, 11.7 Hz, H-30, H-5000), 7.12 (2H, d, J¼015.1 Hz,
H-20, H-6000), 6.61 (2H, 0dd, J¼000 13.4, 11.6 Hz, H-5 , H-3000),
6.42–6.38 (2H, m, H-4 , H-4 ), 6.22–6.17 (2H, m, H-2000,
H-60), 5.95 (1H, dd,0 J¼15.0, 7.8 Hz, H-1000), 5.87 (1H, dd,
J¼15.0, 8.0 Hz, H-7 ), 5.83–5.81 (1H, m, H-100), 5.51 (10H000,
d, J¼9.5 Hz, H-200), 3.97–3.92 (4H, m, Ha-6, Hb-6, Ha-6 ,
Hb-60000), 3.66 (2H, m, H-5, H-50000), 3.03 (6H, s, NCH3,
00
(2H, m, H-5, H-500), 3.05 (6H, s, NCH3, NCH3 ), 0.81 (18H,
00
s, SiC(CH3)3, SiC0(0CH3 )3), [0.04 (6H, s) and 0.00 (6H, s)
Si(CH3)2, Si(CH3 )2]; dC(150 MHz, CDCl3) 192.6 (C-4,
C-4000), 173.7 (C-2, C-2000), 171.3 (C10, C-100), 142.5 (C-800,
C-30), 140.6 (C-60, C-5 ), 135.5 (C-70,00C-40), 123.7 (C-9 ,
C-2 ), 101.7 (C-3, C-300), 68.6 (C-5, C-5 ), 60.7 (C-6, C-600),
00
00
27.0 (NCH3, NCH3 ),0025.5 (SiC(CH3)3, SiC(CH3 )3), 17.95
00
(SiC(CH3)3, SiC(CH3 )3), 20.5 (Si(CH3)2, Si(CH3 )2); m/z
(ESI) (Found: [MþNa]þ, 695.3160. C34H52N2O8Si2
requires [MþNa]þ, 695.3137).
3.1.18.
(3Z,5S,20E,40E,60E,300S,400S,1000E,3000E,5000E,7000Z,50000S)-5-
hydroxymethyl-3-{70-{400-[7000-(50000-hydroxymethyl-10000-
methyl-20000,40000-dioxo-pyrrolidin-30000-ylidene)-7000-
hydroxy-hepta-1000,3000,5000-trienyl]cyclohexen-300-yl}-10-
hydroxy-hepta-20,40,60-trien-10-ylene}-1-methylpyrroli-
dine-2,4-dione (epi,epi-polycephalin C) 1. A mixture of
TFA/water (9:1, 1 ml) was added to 20 (20 mg, 24 mmol)
and immediately removed under reduced pressure. The
process was repeated twice and afforded crude epi,epi-
polycephalin C. Purification by preparative HPLC then
afforded epi,epi-polycephalin C 1 (10.6 mg, 64%) as an
orange amorphous solid, tret 24.5 min, RF 0.57 [CHCl3/
00
NCH30000), 2.76 (1H, br s, H-300), 2.28–2.16 (1H, m, H-4 ),
00
2.09 (2H, br s, Ha-600, Hb-600), 1.86–1.76 (1H, m, Ha-5 ),
1.65–1.46 (1H, m, Hb-500), 0.80 (18H, s, SiC(CH3)3,
SiC(CH30000)3), [0.03 (6H, s) and 20.01 (6H, s) Si(CH3)2,
Si(CH30000)2]; dC (150 MHz, CDCl3) 192.5, 192.47 (C-4,
C-40000), 174.05 (C-2, C-20000), 172.24 (C-10, C-7000), 144.15,
(C-30, C-5000), 143.33 (C-70, C-1000), 142.77, 142.57 (C-50,
000
C-3 ), 130.67 (C-60), 130.00, 129.91, 129.84 (C-40, C-4000,
000
C-2 ), 128.21 (C-100), 127.56 (C-200), 120.97, 120.88 (C-20,

6966
D. A. Longbottom et al. / Tetrahedron 59 (2003) 6955–6966
C-6000), 100.82, 000(0C-3, C-30000),00 69.71, 68.61 (C-5, C-50000),
60.95 (C-6, C-6 ), 44.52 (C-3 ), 43.07 (C-400), 29.66 (C-500)
27.06, 26.98 (NCH3, NCH30000), 25.66 (SiC(CH3)3,
SiC(CH30000)3), 24.01 (C-600), 17.95 (SiC(CH3)3, SiC(CH30000)3),
authors also thank Dr B. Steffan (Thetis Institut fu¨r
biomolekulare Naturstoffforschung) for NMR and CD
spectra of natural polycephalin C.
0000
Si(CH3 )2); m/z (ESI) (Found: [MþNa]þ, 827.4099
C44H64N2O8Si requires [MþNa]þ, 827.4089).
References
3.1.20.
(3Z,5S,20E,40E,60E,300R,400R,1000E,3000E,5000E,7000Z,50000S)-5-
hydroxymethyl-3-{70-{400-[7000-(50000-hydroxymethyl-10000-
methyl-20000,40000-dioxo-pyrrolidin-30000-ylidene)-7000-
hydroxy-hepta-1000,3000,5000-trienyl]cyclohexen-300-yl}-10-
hydroxy-hepta-20,40,60-trien-10-ylene}-1-methylpyrroli-
dine-2,4-dione (polycephalin C) 1. A mixture of TFA/
water (9:1, 1 ml) was added to 23 (8.5 mg, 10.6 mmol) and
immediately removed under reduced pressure. The process
was repeated twice and afforded crude polycephalin
C. Purification by preparative HPLC then afforded poly-
cephalin C 1 (4.5 mg, 74%) as an orange amorphous solid,
tret 24.5 min, [a]D25¼272.5 (c 0.00414, MeOH); nmax (film,
cm21) 3600–3080 (br, OH), 2940, 2922, 1690, 1635, 1590,
1547, 1442, 1404, 1354, 1285, 1256, 1201, 1170, 1132,
1003; dH (600 MHz, CDCl3/CD3OD 1:1, referenced to
residual CH3OH) 7.47 (2H, dd, J¼14.7, 11.9 Hz, H-30,
H-5000), 7.11 (2H, d, J¼015.0 Hz, H-20, H-6000), 6.67 (2H, dd,
J¼14.2, 11.2 Hz, H-5 , H-3000), 6.45–6.34 (2H, m, H-40,
H-4000), 6.27–6.17 (2H, m, H-60, H-2000), 5.98 (1H, d0d,
J¼15.0, 7.8 Hz, H-1000), 5.89 (1H, dd, J¼14.9, 8.1 Hz, H-7 ),
5.84–5.76 (1H, m, H-100), 5.49 (1H, dd,000J0 ¼10.0, 1.8 Hz,
H-200), 3.911, 3.909 (4H, 2£s, Ha-6, Ha-6 , Hb-6, Hb-60000),
3.69 (2H, s, H-5, H-50000), 3.02 (6H, s, NCH3, NCH30000),
2.81–2.72 (1H, m, H-300), 2.27–2.2 (1H, m, H-400), 2.08
(2H, br s, Ha-600, Hb-600), 1.86–1.75 (1H, m, Ha-500), 1.56–
1.46 (1H, m, Hb-500); dC (125 MHz, CDCl3/CD3OD 1:1,
referenced to residual CH3OH) 194.20 (C-4, C-40000), 174.56
(C-2, C-20000), 173.08 (C-10, C-7000), 145.66, 145.61 (C-30,
C-5000), 145.44 (C-10000), 144.63 (C-7000)0, 144.31 (C-3000), 144.08
(C-50), 131.36 (C-6 ), 130.63 (C-200 ), 130.40, 130.24 (C-4,
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Crystallographic Data Centre as supplementary publication
number CCDC-181952. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
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e-mail deposit@ccdc.cam.ac.uk].
000
C-4 ), 128.75 (C-100), 128.08 (C-2 ), 121.06, 120.96 (C-20,
000
C-6 ), 101.37 (C-3, C-30000), 69.34 (C-5, C-50000), 59.27 (C-6,
0000
C-6 ), 45.28 (0C000-300), 43.89 (C-400), 27.72 (C-500), 26.95
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(NCH3, NCH3 ), 24.61 (C-600); m/z (ESI) (Found:
[MþNa]þ, 599.2369. C32H36N2O8 requires [MþNa]þ,
599.2369).
12. Walba, D. M.; Thurmes, W. N.; Haltiwanger, R. C. J. Org.
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Acknowledgements
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7408.
We gratefully acknowledge financial support from the
EPSRC (to D. J. D and D. A. L.), AstraZeneca (to A. J. M.),
and the Novartis Research Fellowship (to S. V. L.). The
14. Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1.