Synthesis of cytochalasans using intramolecular Diels-Alder reactions: An alternative approach to cytochalasin D

Article abstract of DOI:10.1039/a906414a

The macrocycle 25 which has the required functionality around the macrocyclic ring for incorporation into a synthesis of cytochalasin D 1 has been synthesized using an intramolecular Diels-Alder reaction to form the 11-membered ring. The Diels-Alder precursor 24 was prepared in a convergent fashion from the dienyl phosphonate 17, the aldehyde 16 and the pyrrolidinone 21, with phenylselenenylation and oxidative elimination being used to convert the pyrrolidinone 22 into the unstable pyrrolinone 24. The Diels-Alder reaction of the pyrrolinone 24 under high dilution conditions gave the required endo-adduct 25 in a yield of 53% based on the phenylselenopyrrolidinone 23. N-Debenzoylation gave the NH-lactam 26 but preliminary attempts to effect removal of the SEM-groups led to the formation of the methylenedioxy compound 27. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a906414a

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Synthesis of cytochalasans using intramolecular Diels–Alder
reactions: an alternative approach to cytochalasin D
Eric J. Thomas*† and John P. Watts
The Dyson Perrins Laboratory, South Parks Road, Oxford, UK OX1 3QY
Received (in Cambridge, UK) 6th August 1999, Accepted 10th September 1999
The macrocycle 25 which has the required functionality around the macrocyclic ring for incorporation into a
synthesis of cytochalasin D 1 has been synthesized using an intramolecular Diels–Alder reaction to form the 11-
membered ring. The Diels–Alder precursor 24 was prepared in a convergent fashion from the dienyl phosphonate 17,
the aldehyde 16 and the pyrrolidinone 21, with phenylselenenylation and oxidative elimination being used to convert
the pyrrolidinone 22 into the unstable pyrrolinone 24. The Diels–Alder reaction of the pyrrolinone 24 under high
dilution conditions gave the required endo-adduct 25 in a yield of 53% based on the phenylselenopyrrolidinone 23.
N-Debenzoylation gave the NH-lactam 26 but preliminary attempts to effect removal of the SEM-groups led to
the formation of the methylenedioxy compound 27.
The cytochalasans are a group of macrocyclic fungal metabol-
ites which have attracted considerable attention from synthetic
chemists because of their potent biological activity.1,2 The
preceding paper3 reports details of the first synthesis of the
[11]cytochalasan, cytochalasin D 1 using an intramolecular
Diels–Alder reaction of a pyrrolinone to prepare the advanced
intermediate 2.4 One aspect of this synthesis is the introduction
together with ca. 10% of a mixture of diastereoisomeric
epoxides.6 Interestingly the ee of the hydroxyepoxide 4 was
found to correspond to 98% (Mosher’s derivative), significantly
better than that of the starting alcohol, perhaps because of
the preferential formation of the epoxide 6, a diastereoisomer
of epoxide 4, from the Sharpless epoxidation of the enantiomer
of allylic alcohol 3.
The hydroxyepoxide 4 was protected as its 2-trimethylsilyl-
ethoxymethyl (SEM) ether 57 but attempts to open this epoxide
using the lithium enolate of ethyl acetate8 or lithiated 2-methyl-
oxazolines9 or metallated ethoxyacetylenes,10 were unsuccess-
ful. However, ring-opening of the epoxide was eventually
achieved by heating a solution of the epoxide in p-methoxy-
benzyl alcohol containing powdered sodium hydroxide11 at
80 ЊC for three days to give the p-methoxybenzyl ether 7 in
reasonable yield (71%). The relative configurations of this ether
at C(2) and C(4) were checked by deprotection of the 3-hydroxy
group to give the diol 8 which was converted into the cyclic
carbonate 9. The configuration of this cyclic carbonate was
1
confirmed by H NMR, e.g. by the observation of significant
of most of the functionality around the 11-membered ring
including the stereogenic centres at C(18) and C(21) after the
macrocyclisation step, using the conformational preferences of
the macrocyclic ring to control stereochemistry. An advantage
of this approach is that the Diels–Alder product 2, which has
the intact carbon skeleton of the [11]cytochalasans, is formed
relatively early in the synthesis, only eleven linear steps being
required to prepare it from methacrolein. However, a dis-
advantage is that the conversion of this intermediate into
cytochalasin D is quite lengthy. We now report details of pre-
liminary studies of an alternative approach to cytochalasin D 1
using an intramolecular Diels–Alder reaction, in which more
functionality is introduced before the Diels–Alder step.5
NOE enhancements between the cis-disposed substituents
about the 5-membered ring.
Oxidative removal of the p-methoxybenzyl group12 from
the ether 7 gave the diol 10 which was oxidized to the aldehyde
11. Condensation with methoxycarbonylmethylene(triphenyl)-
phosphorane gave the unsaturated ester 12 which was further
protected as its bis-SEM derivative 13. This was hydroborated
regioselectively using 9-borabicyclo[3.3.1]nonane (9-BBN) to
give the primary alcohol 14 and hydrogenation gave the
saturated hydroxyester 15.
Oxidation of this hydroxyester gave the aldehyde 16 which
was condensed with the phosphonate 173,13 under the usual
conditions to give the (E,E,E)-trienyl ester 18 containing
ca. 15% of its (Z,E,E)-isomer (1H NMR), see Scheme 2.
Saponification of this ester gave the acid 19 which was con-
verted into the acyl imidazole 20. This was used to acylate the
N-benzoylpyrrolidinone 2114 to give an epimeric mixture of the
3-alkenoylpyrrolidinones 22. Phenylselenation and oxidative
elimination then gave the unstable pyrrol-2(5H)-one 24. This
was not isolated, rather it was heated in dilute solution in
toluene to give the tricyclic Diels–Alder adduct 25, which
was isolated in a yield of 53% based on the phenylseleno-
pyrrolidinone 23, together with ca. 5% of a mixture of
minor isomeric Diels–Alder adducts which were not fully
characterized.
Results and discussion
The synthesis of the alcohol 15 which corresponds to the
C(14)–C(21) fragment of cytochalasin D is outlined in Scheme
1. The anti-2,4-dimethylhexa-1,5-dien-3-ol 3, ee 84%, together
with ca. 10% of its syn-diastereoisomer, is available from
the reaction between methacrolein and (E)-but-2-enyldiiso-
pinocampheylborane.3 Sharpless epoxidation of this mixture
using (ϩ)-diethyl tartrate gave the hydroxyepoxide 4, 57%,
† Present address: The Department of Chemistry, The University of
Manchester, Manchester, UK M13 9PL.
The structure of the major Diels–Alder adduct 25 was
J. Chem. Soc., Perkin Trans. 1, 1999, 3285–3290
This journal is © The Royal Society of Chemistry 1999
3285

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that in the preceding paper in that more of the functionality
about the 11-membered ring is introduced before the Diels–
Alder step. This should mean that less chemistry is required
after the Diels–Alder cyclisation. The satisfactory yield, 53%,
of the bis-SEM protected Diels–Alder adduct 25 is of interest
but this work was not continued because of the completion of
the total synthesis of cytochalasin D 1 described in the preced-
ing paper.3
Experimental†
For general experimental details see the preceding paper.3
(2R,3S,4S)-2,4-Dimethyl-1,2-epoxyhex-5-en-3-ol 4
(ϩ)-Diethyl -tartrate (12.2 cm3, 71.4 mmol) was added to
titanium() isopropoxide (19.1 cm3, 64.3 mmol) and sieves
(4 Å; 6.5 g) in dichloromethane (200 cm3) at Ϫ20 ЊC. After
stirring for 5 min at Ϫ20 ЊC, the alcohol 3 (9 g, 71.4 mmol) in
dichloromethane (50 cm3) was added dropwise followed by tert-
butyl hydroperoxide in toluene (3 M; 36 cm3). The solution was
stored at Ϫ20 ЊC for 60 h then poured into a solution of ferrous
sulfate (35.6 g) and tartaric acid (14.5 g) in water (160 cm3) at
0 ЊC and the mixture stirred for 30 min at ambient temperature
before extracting with ether (2 × 200 cm3). The organic layer
was dried (MgSO4) and concentrated under reduced pressure.
The residue was dissolved in ether (210 cm3) and a cooled
(0 ЊC) solution of sodium hydroxide (1 M; 120 cm3) in brine
added. The mixture was stirred at 0 ЊC for 1 h then extracted
with ether (2 × 150 cm3) and the ethereal extract dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ether (8:1) as eluant gave
recovered starting material, 0.47 g (5%), followed by the title
compound 4 (5.8 g, 57%), as a colourless oil; [α]D20 ϩ17 (c 1 in
MeOH); νmax/cmϪ1 3475, 3090, 1644, 1245 and 910; δH 1.14
(3 H, d, J 7, 4-CH3), 1.31 (3 H, s, 2-CH3), 2.35 (1 H, br s, OH),
2.42 (1 H, m, 4-H), 2.55 and 2.85 (each 1 H, d, J 5, 1-H), 3.44
(1 H, d, J 4.5, 3-H), 5.04 (2 H, m, 6-H2) and 5.78 (1 H, m, 5-H);
m/z (EI) 142 (Mϩ, 67%), 112 (90) and 86 (100).
(2R,3S,4S)-2,4-Dimethyl-1,2-epoxy-3-(trimethylsilylethoxy-
methoxy)hex-5-ene 5
Diisopropylethylamine (14.5 cm3, 83.5 mmol) was added to
a solution of the alcohol 4 (4.74 g, 33.4 mmol) in CH2C12
(75 cm3) followed by 2-trimethylsilylethoxymethyl chloride
(8.6 cm3, 50.1 mmol) and the solution stirred for 24 h then
diluted with dichloromethane (300 cm3). The solution was
washed with saturated aqueous ammonium chloride (2 ×
150 cm3) and, after re-extracting the aqueous layers with di-
chloromethane (l00 cm3), the organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Chroma-
tography of the residue using light petroleum–ether (15:l) as
eluant gave the title compound 5 (8.66 g, 97%) as a colourless
oil; [α]D20 Ϫ18 (c 1 in MeOH); νmax/cmϪ1 3095, 1645, 1250, 1035,
940, 910, 880 and 840; δH 0.00 (9 H, s, 3 × SiMe), 0.95 (2 H, m,
CH2Si), 1.10 (3 H, d, J 7, 4-CH3), 1.32 (3 H, s, 2-CH3), 2.52
(1 H, m, 4-H), 2.52 and 2.78 (each 1 H, d, J 5, 1-H), 3.13 (1 H,
d, J 5, 3-H), 3.62 (2 H, m, CH2CH2Si), 4.60 and 4.75 (each 1 H,
d, J 8, OHCHO), 6.05 (2 H, m, 6-H2) and 6.83 (1 H, m, 5-H);
m/z (Cl) 287 (Mϩ ϩ 15, 2%), 273 (Mϩ ϩ 1, 0.5) and 215 (22).
Scheme 1 Reagents and conditions: i, (ϩ)-diethyl tartrate, Ti(OPri)4,
4 Å sieves, tert-butyl hydroperoxide, Ϫ20 ЊC, 60 h (57%); ii, diiso-
propylethylamine, 2-trimethylsilylethoxymethyl chloride (97%); iii,
4-methoxybenzyl alcohol, sodium hydroxide, 80 ЊC, 3 days (71%);
iv, aqueous hydrogen fluoride, acetonitrile (63%); v, carbonyl-N,NЈ-
diimidazole, benzene (76%); vi, DDQ, then sodium hydroxide, aqueous
methanol (85%); vii, dimethylsulfoxide, oxalyl chloride, Ϫ50 ЊC then
triethylamine (77%); viii, Ph3P᎐CHؒCO2Me, benzene 80 ЊC, 4 h (95%);
᎐
ix, diisopropylethylamine, 2-trimethylsilylethoxymethyl chloride,
dichloromethane, reflux, 48 h (92%); x, 9-BBN, THF, heat, 1.5 h then
aqueous hydrogen peroxide, sodium hydroxide (76%); xi, 10% Pd/C, H2,
methanol (80%).
assigned on the basis of precedent3,4 and was confirmed by
1
extensive H NMR studies. It corresponds to endo-addition of
the triene onto the less hindered face of the pyrrol-2(5H)-one
as has been observed in all other similar cases.4 The 53%
isolated yield of this Diels–Alder product is of note. However,
problems were encountered in continuing with the synthesis.
N-Deprotection gave the NH-lactam 26, but attempts to intro-
duce a phenylselenenyl group at C(20) using lithium amide
bases and benzeneselenenyl chloride were unsuccessful. More-
over, treatment with aqueous hydrogen fluoride, in an attempt
to remove the two SEM ethers, gave the cyclic acetal 27 rather
than the required diol.
(2R,3S,4S)-2,4-Dimethyl-1-(4-methoxybenzyloxy)-3-(trimethyl-
silylethoxymethoxy)hex-5-en-2-ol 7
p-Methoxybenzyl alcohol (187 cm3, 1.5 mol) was added to the
epoxide 5 (20.5 g, 75.4 mmol) and powdered sodium hydroxide
† In this discussion, the nomenclature devised for the cytochalasans is
used for the Diels–Alder products and compounds derived from them
(see refs. 3, 15).
Summary and conclusions
This approach to a synthesis of cytochalasin D 1 complements
3286
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Scheme 2 Reagents and conditions: i, dimethyl sulfoxide, oxalyl chloride, Ϫ50 ЊC, then triethylamine (78%); ii, butyllithium, 17, add 16, Ϫ78 ЊC, then
hexamethylphosphoramide, 3 h (79%); iii, sodium hydroxide, aqueous ethanol, 6 h; iv, carbonyl-N,NЈ-diimidazole, THF (94% from 18); v, 21,
LiN(SiMe3)2, add 20 (92%); vi, LiN(SiMe3)2, benzeneselenenyl chloride, Ϫ78 ЊC (81%); vii, m-chloroperoxybenzoic acid, aqueous hydrogen peroxide,
Ϫ50 ЊC, 15 min, then 0 ЊC, 10 min; viii, toluene, 80 ЊC, 16 h (53% from 23).
(22.6 g, 565 mmol) and the solution heated at 80 ЊC for
3 days. After cooling to ambient temperature, water (400 cm3)
was added and the mixture extracted with dichloromethane
(2 × 700 cm3). The organic extracts were dried (MgSO4) and
concentrated under reduced pressure. Distillation using a
Kugelröhr at 125 ЊC, 0.5 mmHg, removed the p-methoxybenzyl
alcohol and chromatography of the residue using hexane–ether
(2:1) as eluant gave the title compound 7 (21.8 g, 71%) as a
colourless oil; [α]D20 Ϫ14.4 (c 0.8 in MeOH); [α]D20 Ϫ7.6 (c 0.83 in
CHCl3); νmax/cmϪ1 3500, 3070, 1620, 1520, 1245, 1030, 860 and
840; δH 0.00 (9 H, s, 3 × SiMe), 0.91 (2 H, m, CH2Si), 1.10 (3 H,
d, J 7, 4-CH3), 1.14 (3 H, s, 2-CH3), 2.62 (1 H, m, 4-H), 2.91
(1 H, br s, OH), 3.33 (1 H, d, J 10, 1-H), 3.39 (1 H, d, J 3, 3-H),
diol 8 (35 mg, 0.125 mmol) in benzene (2 cm3) and the solution
3.46 (1 H, d, J 10, 1-H), 3.65 (2 H, m, CH2CH2Si), 3.8 (3 H,
heated under reflux for 2 days. After cooling to ambient tem-
s, OMe), 4.41 and 4.51 (each 1 H, d, J 12, OHCHAr), 4.66
perature, the mixture was washed with water (3 × 2 cm3), dried
(MgSO4) and concentrated under reduced pressure. Chromato-
graphy of the residue using light petroleum–ethyl acetate (5:1)
as eluant gave the carbonate 9 (29 mg 76%), as a colourless oil;
νmax/cmϪ1 3095, 1800, 1620, 1580, 1520, 1310, 1255, 1185, 1100,
and 4.72 (each 1 H, d, J 7, OHCHO), 4.95 (2 H, m, 6-H2), 5.94
(1 H, m, 5-H), and 6.86 and 7.23 (each 2 H, d, J 9, ArH);
m/z (CI) 137 (21%) and 121 (100).
(2R,3S,4S)-2,4-Dimethyl-1-(4-methoxybenzyloxy)hex-5-ene-
2,3-diol 8
1040, 920 and 820; δH 1.03 (3 H, d, J 7, 4-CH3), 1.48 (3 H, s,
2-CH3), 2.79 (1 H, m, 4-H), 3.60 (2 H, s, 1-H2), 3.83 (3 H, s,
OMe), 4.05 (1 H, d, J 10, 3-H), 4.47 and 4.57 (each 1 H, d, J 12,
OHCHAr), 5.09 (2 H, m, 6-H2), 5.83 (1 H, m, 5-H) and 6.90
and 7.25 (each 2 H, d, J 10, ArH); m/z (CI) 324 (Mϩ ϩ 18,
21%), 307 (Mϩ ϩ 1, 2) and 121 (100).
Aqueous hydrogen fluoride (40%; l cm3) in acetonitrile (11 cm3)
was added to the alcohol 7 (l00 mg, 0.24 mmol) and the
solution stirred for l h then poured into dichloromethane
(20 cm3). The mixture was washed with water (12 cm3), dried
(MgSO4) and concentrated under reduced pressure. Chromato-
graphy using light petroleum–ethyl acetate (4:1) as eluant
gave the diol 8 (42 mg, 63%) as a colourless oil; νmax/cmϪ1
3450, 3090, 1620, 1595, 1520, 1300, 1245, 1170, 1080, 1040
and 830; δH 1.13 (3 H, d, J 7, 4-CH3), 1.15 (3 H, s, 2-CH3),
2.46 (1 H, m, 4-H), 2.75 (1 H, d, J 8, 3-OH), 3.05 (1 H, s,
2-OH), 3.37 and 3.63 (each 1 H, d, J 10, 1-H), 3.41 (1 H, m,
3-H), 3.80 (3 H, s, OMe), 4.42 (2 H, s, OCH2Ar), 5.05 (2 H, m,
6-H2), 5.83–6.00 (1 H, m, 5-H) and 6.88 and 7.23 (each 2 H,
d, J 9, ArH).
(2R,3S,4S)-2,4-Dimethyl-3-(trimethylsilylethoxymethoxy)hex-
5-ene-1,2-diol 10
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (565 mg, 2.50
mmol) was added to the ether 7 (465 mg, 1,13 mmol) in
dichloromethane (4.5 cm3) and water (250 cm3). After 20 min,
the mixture was filtered, dichloromethane (20 cm3) was added,
and the mixture was washed with water (10 cm3), dried
(MgSO4) and concentrated under reduced pressure. Chromato-
graphy of the residue using light petroleum–ethyl acetate (6:1)
as eluant gave a mixture of 4-methoxybenzoate esters (458 mg,
1,1-Carbonyldiimidazole (81 mg, 0.5 mmol) was added to the
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97%); νmax/cmϪ1 3445, 3095, 1715, 1615, 1580, 1520, 1255,
1040, 870 and 835; δH 0.00 (9 H, s, 3 × SiMe), 0.92 (2 H,
m, CH2Si), 1.13 (2.1 H, d, J 7, 4-CH3), 1.18 (0.9 H, d, J 7,
4-CH3), 1.28 (2.1 H, s, 2-CH3), 1.50 (0.9 H, s, 2-CH3), 2.63 (1 H,
m, 4-H), 2.78 (0.3 H, br s, OH), 3.43 (0.7 H, d, J l, 3-H), 3.58–
4.17 (5.9 H, m, CH2CH2Si, 3-H, OMe, 1-H2), 4.38 (1.4 H, s,
1-H2), 4.68 (0.7 H, d, J 6, OHCHO), 4.78 and 4.88 (each 0.3 H,
d, J 6, OHCHO), 4.92 (0.7 H, d, J 6, OHCHO), 5.06 (2 H, m,
6-H2), 5.98 (1 H, m, 5-H), 6.90 (2 H, d, J 10, ArH), 7.97 (0.6 H,
d, J 10, ArH) and 8.03 (1.4 H, d, J 10, ArH); m/z (FD) 425
(Mϩ ϩ 1).
Methyl (4R,5S,6S)-4,5-bis(trimethylsilylethoxymethoxy)-4,6-
dimethylocta-2,7-dienoate 13
Diisopropylethylamine (4 cm3, 22.8 mol) was added to the
alcohol 12 (1.57 g, 4.56 mmol) in dichloromethane (20 cm3)
followed by 2-trimethylsilylethoxymethyl chloride (1.6 cm3,
9.13 mmol) and the solution heated under reflux for 48 h. The
solution was then poured into light petroleum (100 cm3) and
washed with aqueous saturated ammonium chloride (2 × 100
cm3), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using hexane–ethyl acetate
(3:1) as eluant gave the title compound 13 (2 g, 92%), as a pale
yellow oil; [α]D20 Ϫ11 (c 0.3 in MeOH); νmax/cmϪ1 3085, 1725,
1650, 1260, 1020, 860 and 835; δH 0.00 (18 H, s, 6 × SiMe), 0.93
(4 H, m, CH2Si), 1.12 (3 H, d, J 7, 6-CH3), 1.38 (3 H, s, 4-CH3),
2.65 (1 H, m, 6-H), 3.42 (1 H, d, J 2, 5-H), 3.50–3.77 (4 H, m,
2 × CH2CH2Si), 3.70 (3 H, s, OMe), 4.69 (4 H, m, 2 × OCH2O),
4.95 (2 H, m, 8-H2), 5.92 (1 H, d, J 16, 2-H), 5.93 (1 H, m, 7-H)
and 6.95 (1 H, d, J 16, 3-H); m/z (CI) 547 (85%), 492 (Mϩ ϩ 18,
33), 463 (27), 447 (22) and 417 (36).
Sodium hydroxide (216 mg, 5.4 mmol) in water (5 cm3) was
added to the mixture of 4-methoxybenzoate esters (458 mg,
1.08 mmol) in methanol (10 cm3) and the mixture stirred for
30 min. Water (5 cm3) was added and the aqueous layer ex-
tracted with dichloromethane (2 × 25 cm3). The organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl
acetate (5:1) as eluant gave the title compound 10 (276 mg, 88%)
as a colourless oil; [α]D20 ϩ10 (c 1 in MeOH); νmax/cmϪ1 3400,
3085, 1635, 1370, 1245, 1020, 860 and 830; δH 0.00 (9 H, s,
3 × SiMe), 0.98 (2 H, m, CH2Si), 1.1 (3 H, s, 2-CH3), 1.12 (3 H,
d, J 7, 4-CH3), 2.63 (1 H, m, 4-H), 2.82 (1 H, dd, J 10, 3, 1-OH),
3.36 (1 H, dd, J 11, 10, 1-H), 3.40 (1 H, d, J 2.5, 3-H), 3.58 (1 H,
m, HCHCH2Si), 3.62 (1 H, s, 2-OH), 3.78 (2 H, m, 1-H, HCH-
CH2Si), 4.65 and 4.85 (each 1 H, d, J 7, OHCHO), 5.04 (2 H,
m, 6-H2) and 5.88 (1 H, m, 5-H); m/z (CI) 308 (Mϩ ϩ 18, 10%)
and 291 (Mϩ ϩ 1, 19).
Methyl (4R,5S,6S)-4,5-bis(trimethylsilylethoxymethoxy)-4,6-
dimethyl-8-hydroxyoct-2-enoate 14
9-Borabicyclo[3.3.1]nonane in THF (0.5 M; 5.1 cm3) was added
to the diene 13 (l g, 2.1 mmol) over 10 min and the mixture
heated under reflux for 1.5 h. The mixture was then cooled to
ambient temperature and water (5 cm3) added dropwise. After
stirring for 10 min, the solution was cooled to 0 ЊC and sodium
hydroxide (3 M; 5.25 cm3) and aqueous hydrogen peroxide
(100 vol; 5.25 cm3) were added dropwise. The mixture was
stirred for 1 h at ambient temperature then water (25 cm3) was
added and the aqueous phase extracted with dichloromethane
(2 × 50 cm3). The organic extracts were washed with brine (25
cm3), dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ether–hexane (2:1) as
eluant gave the title compound 14 (790 mg, 76%), as a colourless
oil; νmax/cmϪ1 3460, 1736, 1665, 1310, 1280, 1250, 1035, 870 and
845; δH 0.00 (18 H, s, 6 × SiMe), 0.92 (4 H, m, 2 × CH2Si), 1.04
(3 H, d, J 7, 6-CH3), 1.41 (3 H, s, 4-CH3), 1.4–2.1 (4 H, m, 6-H,
7-H2, OH), 3.37 (1 H, d, J 2, 5-H), 3.48–3.79 (6 H, m, 8-H2,
2 × CH2CH2Si), 3.73 (3 H, s, OMe), 4.67 and 4.7 (each 1 H,
d, OHCHO), 4.7 (2 H, s, OCH2O), 5.94 (1 H, d, J 16, 2-H) and
6.97 (1 H, d, J 16, 3-H); m/z (CI) 332 (23%), 317 (79), 287 (36)
and 274 (34).
(2S,3S,4S)-2,4-Dimethyl-2-hydroxy-3-(trimethylsilylethoxy-
methoxy)hex-5-enal 11
Dimethyl sulfoxide (3.4 cm3, 47 mmol) in dichloromethane
(10 cm3) was added dropwise to oxalyl chloride (1.9 cm3,
22 mmol) at Ϫ50 ЊC. After stirring for 10 min, the diol 10 (5.7g,
19.7 mmol) in dichloromethane (6 cm3) was added and the
suspension stirred for 10 min. Triethylamine (14 cm3, 0.1 mol)
was added and the mixture stirred a further 10 min at Ϫ60 ЊC
before being allowed to warm to ambient temperature.
Saturated aqueous ammonium chloride (20 cm3) was added and
the mixture extracted with ether (2 × 65 cm3). The organic
extracts were washed with water (2 × 80 cm3), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ether (5:1) as eluant gave the
title compound 11 (4.34 g, 77%) as a colourless oil; [α]D20 ϩ6 (c 1.3
in MeOH); νmax/cmϪ1 3410, 3090, 1725, 1640, 1025, 860, 835;
δH 0.00 (9 H, s, 3 × SiMe), 1.01 (2 H, m, CH2Si), 1.12 (3 H, d,
J 7, 4-CH3), 1.32 (3 H, s, 2-CH3), 2.65 (1 H, m, 4-H), 3.50 (1 H,
d, J l, 3-H), 3.55 and 3.75 (each 1 H, m, HCHCH2Si), 4.64 and
4.88 (each 1 H, d, J 7, OHCHO), 5.12 (2 H, m, 6-H2), 5.87 (1 H,
m, 5-H) and 9.70 (1 H, s, 1-H); m/z (CI) 306 (Mϩ ϩ 18, 0.3%),
157 (21) and 140 (20).
Methyl (4R,5S,6S)-4,5-bis(trimethylsilylethoxymethoxy)-4,6-
dimethyl-8-hydroxyoctanoate 15
A solution of the alkene 14 (753 mg, 1.53 mmol) in methanol
(4 cm3) was added to a suspension of palladium on charcoal
(10%; 64 mg) in methanol (3 cm3) and the mixture stirred under
an atmosphere of hydrogen at 1 atm for 2 h. The reaction was
then filtered through Celite and concentrated under reduced
pressure. Chromatography of the residue using hexane–ether
(1:2) as eluant gave the title compound 15 (608 mg, 80%) as a
colourless oil; νmax/cmϪ1 3450, 1740, 1250, 1040, 860 and 840;
δH 0.00 (18 H, s, 6 × SiMe), 0.91 (4 H, m, 2 × CH2Si), 1.05 (3 H,
d, J 7, 6-CH3), 1.22 (3 H, s, 4-CH3), 1.38 (1 H, m, 6-H), 1.75
(1 H, br s, OH), 1.75–2.15 (4 H, m, 7-H2, 3-H2), 2.39 and 2.46
(each 1 H, dt, J 13, 6, 2-H), 3.27 (1 H, d, J 7, 5-H), 3.53–3.80
(6 H, m, 2 × CH2CH2Si, 8-H2), 3.64 (3 H, s, OMe) and 4.7 (4 H,
m, 2 × OCH2O); m/z (CI) 513 (Mϩ ϩ 19, 0.25%) and 319 (40).
Methyl (4R,5S,6S)-4,6-dimethyl-4-hydroxy-5-(trimethylsilyl-
ethoxymethoxy)octa-2,7-dienoate 12
Methoxycarbonylmethylene(triphenyl)phosphorane (7.6 g,
22.8 mmol) was added to the aldehyde 11 (5.45 g, 18.9 mmol)
in benzene (200 cm3) and the solution heated at 80 ЊC for 16 h
before concentrating under reduced pressure. Chromatography
of the residue using light petroleum–ethyl acetate (8:1) as
eluant gave the title compound 12 (6.15g, 95%) as a colourless
oil; [α]D20 ϩ17.7 (c 0.35 in MeOH); νmax/cmϪ1 3430, 3095, 1745,
1668, 1030, 870 and 845; δH 0.00 (9 H, s, 3 × SiMe), 0.96 (2 H,
m, CH2Si), 1.08 (3 H, d, J 7, 6-CH3), 1.28 (3 H, s, 4-CH3), 2.58
(1 H, m, 6-H), 3.35 (1 H, d, J l, 5-H), 3.53 (1 H, m, HCH-
CH2Si), 3.72 (3 H, s, OMe), 3.78 (1 H, m, HCHCH2Si), 4.42
(1 H, s, OH), 4.63 and 4.87 (each 1 H, d, J 10, OHCHO), 5.07
(2 H, m, 8-CH2), 5.9 (1 H, m, 7-H), 6.07 (1 H, d, J 16, 2-H) and
7.22 (1 H, d, J 16, 3-H); m/z (CI) 362 (Mϩ ϩ 18, 4%) and 317
(80).
Methyl (4R,5S,6S)-4,5-bis(trimethylsilylethoxymethoxy)-4,6-
dimethyl-7-formylheptanoate 16
Following the procedure outlined for the synthesis of the
aldehyde 11, the alcohol 15 (2.7 g, 5.5 mmol) gave, after
chromatography using hexane–ether (2:1) as eluant and
Kugelröhr distillation (210 ЊC, 0.5 mmHg), the title compound
16 (2.1 g, 78%) as a colourless oil; νmax/cmϪ1 1745, 1740, 1250,
3288
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1040, 865 and 840; δH 0.00 (18 H, s, 6 × SiMe), 0.9 (4 H, m,
2 × CH2SiMe), 1.10 (3 H, d, J 7, 6-CH3), 1.23 (3 H, s, 4-CH3),
1.7–2.8 (7 H, overlapping m, 2-H2, 3-H2, 6-H, 7-H2), 3.23 (1 H,
d, J 2, 5-H), 3.6 (4 H, m, 2 × CH2CH2Si), 3.65 (3 H, s, OMe),
4.7 (4 H, m, 2 × OCH2O), 9.73 (1 H, t, J 1.5, CHO); m/z (CI)
510 (Mϩ ϩ 18, 5%), 345 (19%) and 287 (100).
disilazide (6.93 mmol) in THF (20 cm3) at Ϫ78 ЊC via a cannula
and the mixture stirred for 45 min. The imidazole 20 (2.05 g,
3.38 mmol) in THF (25 cm3) was added and the mixture stirred
for 2 h at Ϫ78 ЊC then for 1 h at ambient temperature. Saturated
aqueous ammonium chloride (15 cm3) was added and the
mixture extracted with ether (3 × 75 cm3). The ethereal extracts
were dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue on base washed silica using
light petroleum–ether (4:1) as eluant gave the pyrrolidinone 22
(2.55 g, 92%) as a pale yellow oil; δH 0.00–0.10 (18 H, m,
6 × SiMe), 0.80–1.13 (10 H, m, 4Ј-CH3, 6Ј-CH3, 2 × CH2Si),
1.7–3.0 (15 H, overlapping m), 3.2–3.8 (8 H, m, 5Ј-H, CH2Ph,
3-H, 2 × CH2CH2Si), 4.65–4.85 (5 H, m, 2 × OCH2O, 5-H),
5.43 (0.15 H, m, 9ЈZ-H), 5.50–5.78 (1.85 H, m, 9ЈE-H, 13Ј-H),
6.00–6.25 (3 H, m, vinylic H) and 7.25–7.70 (10 H, ArH);
m/z (DCI-ZAB) 835 (Mϩ ϩ 18), 818 (Mϩ ϩ 1); followed by
recovered lactam 21 (0.75 g).
A cooled solution of the pyrrolidinone 22 (2.55 g, 3.12 mmol)
in THF (20 cm3) was added to lithium hexamethyldisilazide
(3.12 mmol) in THF (20 cm3) at Ϫ72 ЊC via a cannula and the
mixture stirred at this temperature for 30 min before adding
benzeneselenenyl chloride (0.66 g, 3.43 mmol) in THF (l0 cm3).
The mixture was stirred for 2.5 h at Ϫ72 ЊC then saturated
aqueous ammonium chloride (20 cm3) was added and the
mixture allowed to warm to room temperature. Water (15 cm3)
was added, the mixture was extracted with ether (3 × 75 cm3)
and the ethereal extracts were washed with brine (50 cm3),
dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue on base washed silica using
light petroleum–ether (5:1) as eluant gave the pyrrolidinone 23
(2.45 g, 81%) as a 2:1 mixture of diastereoisomers; δH 0.00
and 0.05 (each 9 H, s, 3 × SiMe3), 0.85–1.05 (7 H, m, 2 × CH2Si,
6Ј-CH3), 1.25 (2 H, s, 4Ј-CH3), 1.28 (1 H, s, 4Ј-CH3), 1.70–2.10
(10 H, m, 12Ј-CH3, 14Ј-H3, 6Ј-H, 7Ј-H, 3Ј-H2), 2.40–2.95
(5 H, m, HCHPh, 4-H, 2Ј-H2, 7Ј-H), 3.18–3.40 (3 H, m, 5Ј-H,
HCHPh, 4-H), 3.65 (4 H, m, 2 × CH2CH2Si), 4.45–4.82 (5 H,
m, 5-H, 2 × OCH2O), 5.37–5.83 (2 H, m, 9Ј-H, 13Ј-H), 6.00–
6.30 (3 H, m, 8Ј-H, 10Ј-H, 11Ј-H) and 7.05–7.66 (15 H, m,
ArH); m/z (CI) 564 (3%) and 418 (13).
Methyl (4R,5S,6S,8E,10E,12E)-4,5-bis(trimethylsilylethoxy-
methoxy)-4,6,12-trimethyltetradeca-8,10,12-trienoate 18
Butyllithium in hexanes (1.6 M; 2.8 cm3) was added dropwise
to the phosphonate 17 (1.1 g, 4.73 mmol) in THF (20 cm3)
at Ϫ60 ЊC and the solution stirred at Ϫ60 ЊC for 30 min. The
mixture was then allowed to warm to Ϫ30 ЊC and was stirred at
this temperature for 30 min before being cooled to Ϫ78 ЊC and
added to a solution of the aldehyde 16 (2.1 g, 4.27 mmol)
in THF (15 cm3) at Ϫ78 ЊC. After stirring for 1 h, the cooling
bath was removed and the mixture allowed to warm to ambient
temperature. Hexamethylphosphoramide (3.7 cm3, 21 mmol)
was added and the mixture stirred for 3 h. Ether (60 cm3)
was added and the mixture poured into saturated aqueous
ammonium chloride (17 cm3) then extracted with ether (3 × 25
cm3). The organic extracts were washed with water (3 × 10 cm3),
dried (Na2SO4) and concentrated under reduced pressure.
Chromatography of the residue on base washed silica using
light petroleum (bp 30–40 ЊC)–ether (6:1) as eluant gave the
title compound 18 (1.65 g, 79%) as a colourless oil, a mixture
of 8E:8Z isomers (8:1); νmax/cmϪ1 1740, 1250, 1040, 870 and
845; δH 0.00 (18 H, s, 6 × SiMe), 0.91 (4 H, m, 2 × CH2Si), 1.02
(3 H, d, J 7, 6-CH3), 1.22 (3 H, s, 4-CH3), 1.72–2.10 (10 H, m,
12-CH3, 14-H3, 3-H2, 6-H, 7-H), 2.29–2.56 (3 H, m, 2-H2, 7-H),
3.29 (1 H, d, J 2, 5-H), 3.62 (4 H, m, 2 × CH2CH2Si), 3.63 (3 H,
s, OMe), 4.73 (4 H, m, 2 × OCH2O), 5.39 (0.1 H, m, 9Z-H), 5.6
(1.9 H, m, 9E-H, 13-H) and 6.0–6.2 (3 H, m, 8-H, 10-H, 11-H);
m/z (CI) 508 (Mϩ ϩ 18, 38%), 453 (26), 425 (25) and 395 (28).
Sodium hydroxide (0.68 g, 17 mmol) in water (1.1 cm3) was
added to the ester 18 (2.08 g, 4.2 mmol) in ethanol 15 cm3 and
the mixture stirred for 4 h at room temperature. An ice-cold
solution of tartaric acid (6.3 g, 42 mmol) in water (60 cm3) was
added and the aqueous phase extracted with ether (4 × 50 cm3).
The ethereal extracts were dried (Na2SO4) and concentrated
under reduced pressure to give the acid 19 (2.1 g) as a pale
yellow oil, used without further purification; δH 0.00 (18 H, s,
6 × SiMe3), 0.93 (4 H, m, 2 × CH2Si), 1.05 (3 H, d, J 7, 6-CH3),
1.25 (3 H, s, 4-CH3), 1.73–2.12 (10 H, m, 12-CH3, 14-H3, 3-H2,
6-H, 7-H), 2.42–2.60 (3 H, m, 2-H2, 7-H), 3.3 (1 H, d, J 2, 5-H),
3.65 (4 H, m, 2 × CH2CH2Si), 4.74 (4 H, m, 2 × OCH2O), 5.44
(0.1 H, m, 9Z-H), 5.65 (1.9 H, m, 9E-H, 13-H) and 5.93–6.22
(3 H, m, vinylic H).
(16S,17S,18R)-2-Benzoyl-17,18-bis(trimethylsilylethoxy-
methoxy)-16,18-dimethyl-10-phenyl[11]cytochalasa-6(7),13-
diene-1,21-dione 25
A solution of hydrogen peroxide (100 vol; 2.85 cm3) in water
(1.1 cm3) was added to a solution of the selenide 23 (2.45 g, 2.52
mmol) in chloroform (175 cm3) at Ϫ50 ЊC. A solution of m-
chloroperoxybenzoic acid (510 mg, 2.52 mmol) in chloroform
(90 cm3) was added, and the mixture stirred at Ϫ50 ЊC for 15
min then at 0 ЊC for 10 min before being washed with saturated
aqueous sodium bicarbonate (2 × 50 cm3), water (50 cm3) and
brine (50 cm3) to provide a solution of the pyrrolinone 24;
δH 7.94 (1 H, d, J 2, 4-H). After drying (Na2SO4), the solution
of the pyrrolinone 24 was added to degassed toluene (900 cm3)
and the solution heated at 80 ЊC for 16 h. After concentration
under reduced pressure, chromatography of the residue using
light petroleum–ether (8:1) as eluant gave the title compound
25 (1.09 g, 53%) as a colourless oil; νmax/cmϪ1 (CHCl3) 1735,
1695, 1684, 1600, 1290, 1250, 1055, 1020, 862 and 840; δH 0.00
and 0.05 (each 9 H, s, 3 × SiMe), 0.92 (7 H, m, 2 × CH2Si,
16-CH3), 1.05 (3 H, d, J 6, 5-CH3), 1.15 (3 H, s, 18-CH3), 1.55–
1.97 (5 H, m, 15-H, 16-H, 19-H2, 20-H), 1.73 (3 H, s, 6-CH3),
2.35–2.53 (2 H, m, 5-H, 15-H), 2.65 (1 H, m, 8-H), 2.73 (1 H,
dd, J 14, 9, 10-H), 3.05 (1 H, d, J 14, 10-H), 3.15 (1 H, m, 4-H),
3.35 (1 H, m, 17-H), 3.40–3.85 (4 H, m, 2 × CH2CH2Si), 4.32
(1 H, m, 3-H), 4.37 (1 H, m, 20-H), 4.57–4.87 (4 H, m, 2 ×
OCH2O), 5.20 (1 H, m, 14-H), 5.65 (1 H, br s, 7-H), 6.12 (1 H,
dd, J 13, l0, 13-H) and 7.13–7.57 (10 H, m, ArH); m/z (FAB)
833 (Mϩ ϩ 18); a second fraction (118 mg, 5%) contained a
mixture of minor diastereoisomers.
Carbonyl 1,1Ј-diimidazole (0.71 g, 4.4 mmol) was added to a
solution of the acid 19 (2.1 g, 3.65 mmol) in THF (25 cm3) and
the mixture stirred at room temperature for 6 h before being
diluted with ether (40 cm3). The ethereal solution was washed
with ice-cold water (30 cm3) and brine (25 cm3), dried (Na2SO4)
and concentrated under reduced pressure to give the acyl
imidazole 20 (2.1 g, 94%), as a viscous colourless oil used with-
out further purification; δH 0.00 (18 H, s, 3 × SiMe), 0.91 (4 H,
m, 2 × CH2Si), 1.08 (3 H, d, J 7, 6-CH3), 1.28 (3 H, s, 4-CH3),
1.73–2.23 (10 H, m, 12-CH3, 14-H3, 3-H2, 6-H, 7-H), 2.47 (1 H,
m, 7-H), 3.00 and 3.15 (each 1 H, m, 2-H), 3.38 (1 H, d, J l,
5-H), 3.63 (4 H, m, 2 × CH2CH2Si), 4.75 (4 H, m, 2 × OCH2O),
5.44 (0.1 H, m, 9Z-H), 5.55–5.78 (1.9 H, m, 9E-H, 13-H), 6.02–
6.2 (3 H, m, vinylic H) and 7.09, 7.53 and 8.23 (each 1 H, s,
imid-H).
(5S)-l-Benzoyl-3-[(4R,5S,6S,8E,10E,12E)-4,5-bis(trimethyl-
silylethoxymethoxy)-1- oxo-4,6,12-trimethyltetradeca-8,10,12-
trienyl]-5-phenylmethyl-3-phenylselenopyrrolidin-2-one 23
A cooled solution of the pyrrolidinone 21 (2 g, 7.1 mmol) in
THF (20 cm3) was added to a solution of lithium hexamethyl-
J. Chem. Soc., Perkin Trans. 1, 1999, 3285–3290
3289

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(16S,17S,18R)-17,18-Bis(trimethylsilylethoxymethoxy)-16,18-
dimethyl-10-phenyl[11]cytochalasa-6(7),13-diene-1,21-dione 26
17-H), 4.09 (1 H, ddd, J 19, 11.5, l, 20-H), 4.90 and 5.23 (each
1 H, s, OHCHO), 5.24 (1 H, ddd, J 16, 12, 4, 14-H), 5.32 (1 H,
br s, NH), 5.49 (1 H, br s, 7-H), 6.26 (1 H, ddd, J 16, 10.5, 3,
13-H) and 7.07–7.38 (5 H, m, ArH); m/z (CI) 481 (Mϩ ϩ 18,
3%), 464 (Mϩ ϩ 1, l00) and 434 (12).
A solution of the Diels–Alder product 25 (1.06 g, 1.3 mmol) in
methanol (10 cm3) was added to a solution of sodium hydroxide
(1.04 g, 26 mmol) in methanol (15 cm3) containing water (1.2
cm3) and the mixture stirred for 2.5 h before being poured into
water (100 cm3) and extracted into ether (3 × 100 cm3). The
ethereal extracts were dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ether (3:2) as eluant gave the title compound 26
(817 mg, 89%) as a white powder; [α]20 Ϫ84 (c 0.44 in MeOH);
νmax/cmϪ1 (CHCl3) 3420, 1690, 1250, 1055, 1020, 960, 940; δH
0.00 and 0.05 (each 9 H, s, 3 × SiMe), 0.9 and 1.0 (each 2 H, m,
CH2Si), 1.06 (3 H, d, J 8, 16-CH3), 1.14 (3 H, d, J 7, 5-CH3),
1.16 (3 H, s, 18-CH3), 1.65 (3 H, m, 16-H, 19-H2), 1.72 (3 H, 2,
6-CH3), 1.80 (1 H, m, 15-H), 1.90 (1 H, m, 20-H), 2.40 (1 H, m,
5-H), 2.42 (1 H, dd, J 14, 10, 10-H), 2.49 (1 H, m, 8-H), 2.55
(1 H, m, 15-H), 2.70 (1 H, dd, J 14, 4, 10-H), 3.05 (1 H,
m, 4-H), 3.25 (1 H, m, 3-H), 3.39 (1 H, s, 17-H), 3.53 (1 H, m,
HCHCH2Si), 3.63 (2 H, m, 2 × HCHCH2Si), 3.93 (1 H, m,
HCHCH2Si), 4.66 (1 H, m, 20-H), 4.68, 4.72, 4.83 and 4.93
(each 1 H, d, J 7, OHCHO), 5.25 (1 H, ddd, J 15, 11, 4, 14-H),
5.39 (1 H, br s, NH), 5.45 (1 H, br s, 7-H), 6.35 (1 H, ddd, J 15,
10, 1.5, 13-H), 7.07–7.38 (5 H, m, ArH); m/z (CI) 784
(Mϩ ϩ 73, 12%), 729 (Mϩ ϩ 18, 43), 712 (Mϩ ϩ 1, 3), 594 (35),
564 (43), 536 (29), 506 (21), 464 (100) and 416 (90).
Acknowledgements
We thank the EPSRC (SERC) and Astra-Zeneca (ICI Pharma-
ceuticals) for support (to J. P. W.) under the CASE Scheme and
Dr. A. Brewster for many helpful discussions.
References
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(16S,17S,18R)-16,18-Dimethyl-17,18-methylenedioxy-10-
phenyl[11]cytochalasa-6(7),13-diene-1,21-dione 27
Aqueous hydrogen fluoride in acetonitrile (150 µl from a
stock solution comprising 40% hydrogen fluoride, 1 cm3 in
acetonitrile 3 cm3) was added to a solution of the macrocycle 26
(15 mg, 0.02 mmol) in acetonitrile (150 cm3) and the mixture
stood at room temperature for 6 h before diluting with dichloro-
methane (5 cm3), washing with water (2 cm3), drying (MgSO4)
and concentrating under reduced pressure. Chromatography
of the residue using light petroleum–ether (1:3) as eluant
gave the title compound 27 (5 mg, 55%) as a white solid, mp
216–217 ЊC (Found: Mϩ 463.2722. C29H37NO4 requires M,
463.2725); νmax/cmϪ1 3420, 1700 1085 and 990; δH 1.18 (3 H, d,
J 6.5, 16-CH3), 1.19 (3 H, d, J 6, 5-CH3), 1.23 (3 H, s, 18-CH3),
1.73 (3 H, s, 6-CH3), 1.80–1.95 (4 H, m, 15-H, 16-H, 19-H2),
2.02 (1 H, m, 20-H), 2.40 (1 H, dd, J 13.5, 9.5, 10-H), 2.42 (1 H,
m, 5-H), 2.52 (1 H, m, 8-H), 2.72 (2 H, m, 10-H, 15-H), 3.00
(1 H, dd, J 6.5, 3, 4-H), 3.24 (1 H, m, 3-H), 3.32 (1 H, br s,
Paper 9/06414A
3290
J. Chem. Soc., Perkin Trans. 1, 1999, 3285–3290