Palladium catalysed formal 6-endo-trig approaches to pumiliotoxin alkaloids: Interception of the elusive cyclopropyl intermediate

Article abstract of DOI:10.1039/a909774k

Intramolecular Heck cyclisation of (E)-vinyl bromides leads to indolizidines, related to pumiliotoxin alkaloids, in which the stereochemistry of the trisubstituted double bond undergoes inversion. A cyclopropyl intermediate, which is believed to be respon

Full text of DOI:10.1039/a909774k

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Palladium catalysed formal 6-endo-trig approaches to pumiliotoxin
alkaloids: interception of the elusive cyclopropyl intermediate
Stephanie Feutren, Helena McAlonan, David Montgomery and Paul J. Stevenson*
School of Chemistry, The Queen’s University of Belfast, Belfast, UK BT9 5AG
Received (in Cambridge, UK) 13th December 1999, Accepted 28th February 2000
1
Intramolecular Heck cyclisation of (E)-vinyl bromides leads to indolizidines, related to pumiliotoxin
alkaloids, in which the stereochemistry of the trisubstituted double bond undergoes inversion. A cyclopropyl
intermediate, which is believed to be responsible for the double bond inversion, has been intercepted by forcing
an ‘early’ β-hydride elimination on this species. The relative stereochemistry of this cyclopropyl intermediate
determines the regioselectivity of the final β-hydride elimination. In this case all three β-hydride eliminations
were stereochemically permitted, giving rise to a mixture of three isomeric products, differing in the position of a
double bond. (Z)-Vinyl bromides were found to be less reactive than (E)-vinyl bromides, but on cyclisation gave
the required conjugated diene, with inversion of the vinyl bromide stereochemistry, as the sole reaction product.
This methodology will allow rapid stereoselective access to the diene-based pumiliotoxin alkaloids.
is the same as in the pumiliotoxins.6 Due to the scarcity of
Introduction
pumiliotoxins from the natural source and their biological
activity, there has been intense interest in the synthesis of these
compounds, and this has been the subject of a review.7 To date,
most biological studies on the pumiliotoxin alkaloids have been
performed with synthetic material.8
The major problem in pumiliotoxin synthesis is control of
the stereochemistry at the trisubstituted, exocyclic double
bond. A number of ingenious solutions to this problem have
emerged based on iminium ion chemistry,9 aldol chemistry,10
organochromium chemistry,11 organopalladium chemistry12
and recently, for the allopumiliotoxins, reductive cyclisation of
ynals.13
Recently we became interested in the application of intra-
molecular Heck chemistry to assemble the (Z)-trisubstituted
double bond, found in the pumiliotoxins and homopumilio-
toxins, Fig. 1. The diene analogues of the natural pumiliotoxins
are interesting substrates to probe the effect of the hindered C8
hydroxy group on the biological activity. Alternatively, selective
functionalisation of the endocyclic double bond could in
principle lead to natural pumiliotoxins or allopumiliotoxins.
The pumiliotoxin alkaloids, isolated from defensive skin
secretions of amphibians, comprise an indolizidine skeleton
with a (Z)-alkylidene side chain (Fig. 1).1 Pumiliotoxin 307A
was first discovered as one of the three major alkaloids in the
Panamanian poison frog Dendrobates pumilio.2 Since then
many other members of this class of alkaloid, at present over
forty, with variation in the alkyl side chain have been isolated
and characterised. The vast majority of pumiliotoxins bear a
tertiary hydroxy group at C8 and the allopumiliotoxins bear
an additional hydroxy group at C7.3 Recently, a pumiliotoxin
devoid of a C8 hydroxy group, deoxypumiliotoxin 251H,
has been isolated as a minor component from the Ecuadorean
frog Epipedobates tricolor.4 Diene-based quinolizidines, for
example homopumiliotoxin 221F, have been isolated from the
Madagascar frog Mantella, in which the tertiary alcohol at C8
is replaced with a double bond.5 Due to the small amounts of
quinolizidines isolated these structures remain tentative, but it
is assumed that the trisubstituted double bond stereochemistry
Results and discussion
The aim of this study was to investigate whether the indoliz-
idine pumiliotoxin skeleton, could be stereoselectively
assembled by cyclisation of vinyl bromide 8. The synthesis of
the starting material for this investigation is summarised in
Schemes 1 and 2.
Tertiary amines are notoriously difficult compounds to
handle so internal amine protection was sought. This was
readily accomplished by employing pyroglutamates as pre-
cursors. The advantage of having the carbonyl group contained
in the five membered ring is that it eliminates hindered rotation
and makes the proton NMR spectra simple and easy to inter-
pret. The synthesis of the pyrrolidinone fragment 1 is detailed
in Scheme 1. N-Benzyl pyroglutamic acid ethyl ester is available
from glutamic acid using Rapoport’s procedure,14 and was the
starting point for this study. Introduction of the 5-isopropenyl
group was readily achieved by reaction of the ester with two
equivalents of methylmagnesium iodide followed by dehydra-
tion. Reductive removal of the N-benzyl group using sodium in
Fig. 1 Representative examples of the different classes of pumiliotoxin
alkaloids.
DOI: 10.1039/a909774k
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137
This journal is © The Royal Society of Chemistry 2000
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Table 1 Products of intramolecular Heck cyclisations of compound 8
Amount of products formed (%)
9
10
11
12
Conditions
30
28
17
55
46
14
15
26
14
0
0
41
1 h, 80 ЊC
RT, 18 h, Et4NCl
RT, 56 h, TlOAc
product is consistent with a stereoselective antiperiplanar
elimination of hydrogen bromide.
Alkene stereochemistry was readily assigned by proton NMR
spectroscopy. Hence, the vinyl proton in the (Z)-isomer is
predicted to have a higher chemical shift than that of the
corresponding proton in the (E)-isomer because it is cis to
the carboxy group. In the event the chemical shift values of the
(E)- and (Z)-isomers were found to be 7.52 ppm and 6.88 ppm
respectively, close to the empirically calculated values of 7.66
ppm and 6.73 ppm respectively.17
Scheme 1 Reagents and conditions: (i) MeMgI, THF–Et2O; (ii)
thionyl chloride, THF, Ϫ78 ЊC; (iii) Na, NH3; (iv) α-methylbenzyl
isocyanate, toluene, 108 ЊC.
Esterification under mildly basic conditions gave the corre-
sponding methyl esters with no scrambling of the double bond
stereochemistry. At this stage the stereoisomers were separated
by flash chromatography, aided by the (E)-isomer having a
higher Rf value than the (Z)-isomer. Reduction of the ester to
the alcohol and conversion of the alcohol to bromide 5 pro-
ceeded smoothly. Some batches of allylic bromide 5 were con-
figurationally unstable and could not be stored, whilst other
batches were stable. It is therefore recommended that this com-
pound is used as soon as it is made. Finally, coupling of amide 1
to bromide 5, was effected using sodium hydride as base in
anhydrous THF as solvent and gave the starting material 8, in
85% yield, for the cyclisation study.
The results of the intramolecular Heck cyclisations on
substrate 8 are summarised in Scheme 3 and Table 1.
Scheme 2 Reagents and conditions: (i) Br2, CH2Cl2, 25 ЊC; (ii) NaOH,
H2O, 40 ЊC; (iii) NaOH, H2O, DMSO, MeI; (iv) DIBAL-H, toluene,
Ϫ78 ЊC; (v) Ph3P, Br2, CH3CN; (vi) Br2, CH2Cl2, 0 ЊC then Et3N; (vii)
NaBH4, EtOH.
liquid ammonia gave the key intermediate 1 in 50% overall yield
for the three steps. The optical purity of this material was
determined to be at least 96% ee by making urethane derivatives
2a,b with both (R)- and (S)-α-methylbenzyl isocyanate, and
measuring the relative amounts of diastereoisomers present.15
It is assumed that the isocyanate supplied by the Aldrich Chem-
ical Company was optically pure. These urethanes are ideal
derivatives for measuring the optical purity of cyclic amides
because the hydrogen bond between the NH and ring carbonyl
group freezes out one conformation and gives rise to sharp
signals in proton NMR spectra.
Since this was merely a feasibility study, a hydrophobic,
stereochemically pure (E)-vinyl bromide was sought. The
required vinyl bromide precursor was readily available by brom-
ination dehydrobromination of nonenoic acid (Scheme 2). The
role of the carbonyl group was to ensure that the dehydro-
bromination reaction was completely regioselective, giving only
the 2-bromoalkene on elimination. When dibromide 3 was
treated with aqueous sodium hydroxide according to James’s
original procedure,16 the steroselectivity of the elimination
reaction was moderate, giving a 5.7:1 mixture of (E)- and
(Z)-double bond isomers 4 in 68% overall yield for the two
steps. The production of the (E)-vinyl bromide as the major
Scheme 3 Reagents and conditions: (i) Pd(OAc)2, Ph3P, K2CO3,
CH3CN.
On heating substrate 8 under normal Heck conditions, three
cyclic compounds 9–11 were formed in 55% combined yield.
The conjugated diene 9 was assigned by the presence of a
singlet in the vinyl region at δ 6.21 ppm in the proton NMR
spectrum. The structure of the major product 10 was confirmed
by the simplicity of its proton NMR spectrum arising from the
loss of chirality. Structure 11 was readily assigned by the pres-
ence of the alkene methylene signals at δ 4.81 ppm and 4.92
ppm and the methylene group between the two alkenes coming
as an AB multiplet centred at δ 2.92 ppm in the proton NMR
spectrum.
It was somewhat surprising to see how little of the conju-
gated diene 9 (30%) was formed, the unconjugated isomer 10
1130
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being the major product (Table 1, entry 1). However, it is con-
ceivable that β-hydride elimination to give 9 is retarded as the
hydrogen on the newly formed alkene and the pendent alkyl
group approach each other as the system becomes planar.
Formation of bis-exocyclic alkene 11 was completely unex-
pected and suggested that the final β-hydride elimination into
the ring was difficult. Exocyclic β-hydride eliminations have
previously been observed in sterically constrained systems, so
this reaction is not without precedent.18 Formation of 10 as
the major product is interesting and has implications for the
relative stereochemistry of the intermediate organopalladium
species 14. β-Hydride elimination can only take place when the
palladium and hydrogen are cis. In principle there are two pos-
sible diastereoisomeric organopalladium intermediates, and the
formation of 10 indicates that the intermediate diastereoisomer
14 is the one in which the hydrogen and palladium are cis.
However this argument is not totally conclusive as 10 could
arise from a subsequent isomerisation of 9 or 11.
Tetraalkylammonium halides can have a dramatic effect on
the outcome of Heck reactions.19 The result of addition of one
equivalent of tetraethylammonium chloride to the reaction
mixture is summarised (Table 1, entry 2). The same products,
9–11, were formed as before, but in different amounts. In par-
ticular the relative amount of 11 is up, mainly at the expense of
10, suggesting 11 may be a kinetic product of the reaction.
Heating the reaction mixture for one hour after consumption
of starting material, gave the same isomer mixture as entry 1
Table 1, strongly suggesting that 11 may be a kinetic product.
The reaction mixtures were complex due to all three pos-
sible β-hydride eliminations taking place, with poor selectivity.
Thallium salts are capable of having a profound influence in
the direction of β-hydride elimination.20 It is believed that the
thallium removes the halide from the intermediate organo-
palladium species, facilitating elimination, and often giving
only one isomer. One equivalent of thallium acetate was intro-
duced into the reaction with a view to increasing the selectivity
of β-hydride elimination (Table 1, entry 3). The outcome of this
reaction was completely unprecedented, with the major product
now being the vinylcyclopropane 12. The gross structure of this
adduct was readily assigned based on the diastereotopic hydro-
gens within the cyclopropane methylene group appearing as an
AB multiplet in the proton NMR spectrum at δ 0.46 ppm and
0.56 ppm, J = 5.6 Hz. Cyclopropane 12 was formed as a single
diastereoisomer with complete stereocontrol at the two newly
created chiral centres and as only the (E)-alkene. The relative
stereochemistry of 12 was determined by NOE difference
spectroscopy. Hence, saturation of the methyl group adjacent to
the cyclopropane ring gave a 7.6% NOE to the adjacent
methine proton and a 6.1% NOE enhancement to the vinyl
proton, supporting the stereochemistry postulated. This is the
first example of an intramolecular Heck reaction leading to
a vinylcyclopropane product in a conformationally flexible
system.
The stereochemistry of compounds 9–11 was assigned by
irradiating the alkene triplets in the proton NMR spectra and
observing strong NOE enhancements to the NCH2 protons of
5.0–6.8%. To our surprise this suggested that the trisubstituted
double bond had undergone inversion on cyclisation. Although
vinylpalladium species are configurationally stable, reports of
inversion of configuration on cyclisation have previously been
noted,21 and a mechanism involving cyclopropane inter-
mediates has been proposed.22 It should also be noted that
formal 6-endo-trig cyclisation of a vinyl radical also proceeds
via a cyclopropyl intermediate.23
A unifying mechanism for the formation of products 9–12
is outlined in Scheme 4. 5-exo-trig followed by a consecutive
3-exo-trig cyclisation gave the key cyclopropyl intermediate 13.
In the presence of thallium acetate, bromide is removed from
this intermediate and this triggers a β-hydride elimination and
gave tricyclic compound 12 as the major product. Isolation of
product 12 allows an unambiguous assignment of stereo-
chemistry in intermediate 13, at the two newly formed chiral
centres, and confirms that cyclopropanes will readily form
under these reaction conditions. Although vinylcyclopropanes
have previously been observed in intramolecular Heck reac-
tions,24 their presence was limited to conformationally inflexible
systems in which the alkylpalladium was generated inside a
ring before the final β-hydride elimination. In the absence
of thallium acetate, cyclopropyl intermediate 13 undergoes
rotation around the exo σ-bond to give the correct conform-
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137
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ation for a fragmentation which leads to 14 with inversion
of alkene stereochemistry. The fragmentation, which is the
reverse of 3-exo-trig cyclisation, is highly stereoselective giving
(R)-configuration at the newly generated chiral centre bearing
palladium. Interestingly, with this diastereoisomer all three
β-hydride eliminations are stereochemically permissible and it is
gratifying that all products 9–11 are produced.
The corresponding cyclisation with an electron withdrawing
group on the alkene double bond was next investigated (Scheme
5). This should electronically encourage direct 6-endo-trig
adopted but the base for the dehydrobromination was changed
to triethylamine since tertiary amines are known to give pre-
dominantly (Z)-vinyl bromides predominately on elimination.26
An aldehyde was used instead of a carboxylic acid to circum-
vent the known ready decarboxylation of these substrates.27
Hence, bromination of hex-2-enal at 0 ЊC followed by immedi-
ate dehydrobromination using triethylamine gave only the
(Z)-vinyl bromide isomer 6 in 99% crude yield for the one pot
procedure.28 The corresponding (E)-isomer could not be
detected by 13C NMR spectroscopy of the crude reaction mix-
ture. It is suspected that the (E)-alkene is equilibrating to give
exclusively the (Z)-alkene under the reaction conditions. To test
this hypothesis a sample of an (E)-2-bromoalk-2-enal was
required. However attempts to oxidise (E)-2-bromonon-2-en-1-
ol with the Dess–Martin periodinane gave exclusively (Z)-2-
bromonon-2-enal. Although this was not what was required it
does demonstrate that the isomerisation of (E)-2-bromonon-2-
enal to (Z)-2-bromonon-2-enal is very facile indeed.
Reduction of the aldehyde 6 gave an allylic alcohol which
was converted to 18 via the dibromide 7 as previously described
for 8.
Scheme 6 Reagents and conditions: (i) Pd(OAc)2, Ph3P, K2CO3,
CH3CN, 12 h, 80 ЊC.
The cyclisation of 18 was much slower that that of substrate
8 requiring a 12 h reflux to go to completion, but it gave
exclusively the conjugated diene 19 as the sole reaction product
in 56% isolated yield (Scheme 6). Again, the stereochemistry of
the exocyclic trisubstituted double bond was assigned by NOE
difference spectroscopy. Saturation of the vinyl singlet at δ 5.88
ppm gave an enhancement of 4.7% to the triplet at δ 5.31 ppm
confirming the vinyl bromide changed stereochemistry on cyclis-
ation. With the alkyl group on the opposite side of the exocyclic
double bond, the final β-hydride elimination to give the endo-
cyclic conjugated double bond is now favoured. There are a
number of reasons why the cyclisation is slower than with the
corresponding (E)-vinyl bromide. Firstly, the pendent alkyl
group is now cis to the bromide and it would be expected that
the initial oxidative addition is not as facile as it was with the
corresponding (E)-isomer. Secondly, it is likely that in form-
ation of the tricyclic intermediate 20, by a 5-exo-trig pathway,
interaction between the propyl group and the palladium retards
the rate of this reaction. The same interaction would also retard
the subsequent 3-exo-trig cyclisation of 20. It is difficult to
quantify which of the above factors is more influential but
clearly there will be a cumulative effect leading to an overall
slower rate for cyclisation.
Scheme 5 Reagents and conditions: (i) CaOCl, CO2, H2O–CH2Cl2;
(ii) dioxane, H2O, NaHCO3, 105 ЊC; (iii) TPAP, N-methylmorpholine
N-oxide, CH2Cl2, 0 ЊC; (iv) Pd(OAc)2, Ph3P, K2CO3, CH3CN, 80 ЊC.
cyclisation with preservation of the vinyl bromide stereo-
chemistry. The starting material for this study, 15, was readily
available from allylic chlorination of substrate 8,25 conversion
of the chloride to the alcohol and oxidation to aldehyde 15. The
overall yield for the three stage sequence was 40%, with the
poorest yield being for the allylic chlorination at 62%.
Substrate 15 cyclised in boiling acetonitrile under standard
Heck conditions and gave 16 and 17 as a 2:1 mixture of double
bond isomers. If heating was continued for a further hour then
the isomer ratio changed to 94:6, confirming equilibration of
17 to 16. The fact that so little of the conjugated diene, 17,
formed, immediately suggested that the double bond had
indeed undergone inversion on cyclisation. This was confirmed
by NOE difference spectroscopy where irradiation of the triplet
at δ 5.89 ppm in substrate 17 gave a strong enhancement of
6.3% of one of the diastereotopic protons at δ 4.71 ppm of the
NCH2 group and no enhancement of the other vinyl signal at
δ 7.34 ppm. Isomer 16 displayed two singlets at δ 4.08 and 3.06
respectively in the proton NMR spectrum corresponding to
In conclusion, the palladium chemistry studied proved
much more subtle and complex than initially envisaged and a
number of valuable mechanistic insights have been gleaned.
This methodology is currently being applied to the synthesis of
the tentatively assigned homopumiliotoxin 221F (Fig. 1).
NCH C᎐C and N᎐C–CH –C᎐C groups respectively. Again, the
᎐
᎐
᎐
2
2
spectrum was simple because chirality was lost during the elim-
ination. Irradiation of the vinyl triplet at δ 5.57 ppm gave a
NOE of 6.8% to the singlet at δ 4.08 ppm, confirming inversion
of the trisubstituted double bond on cyclisation. Even with
electron deficient alkenes the initial attack is at the α-carbon.
In order to gain access to the pumiliotoxin skeleton with the
correct trisubstituted (Z)-double bond stereochemistry a sub-
strate containing a (Z)-vinyl bromide was required (Scheme 2).
A similar strategy to that adopted for the synthesis of 5 was
Experimental
General
Melting points were recorded using a Kofler hot stage appar-
atus and are uncorrected. IR spectra were recorded on a Perkin-
Elmer Model 983G instrument coupled to a Perkin-Elmer 3700
Data Station as potassium bromide (KBr) disks, or films
1132
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137

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(liquids). Proton nuclear magnetic resonance (NMR) spectra
were recorded at 300 MHz and 500 MHz using General Electric
QE 300, Bruker DPX 300 and DRX 500 NMR spectrometers.
Chemical shifts are given in parts per million (δ) downfield
from tetramethylsilane as internal standard and coupling
constants are given in hertz. The following abbreviations are
used: s singlet, d doublet, t triplet, q quartet, m multiplet and br
broad. Mass spectra were recorded using Double Focusing
Triple Sector VG Auto Spec and accurate molecular masses
were determined by the peak matching method using
perfluorokerosene as standard reference and were accurate
to within 0.006 amu. Microanalyses were obtained using a
Perkin-Elmer 2400 CHN elemental analyser. Optical rotations
were determined on a Perkin-Elmer precision polarimeter
Model 241, using specified solvent and concentration at the
D-line 589 nm and at ambient temperature. Analytical TLC was
carried out on Merck Kieselgel 60254 plates and the spots visu-
alised using a Hanovia Chromatolite UV lamp. Flash chrom-
atography was effected using Merck Kielselgel 60 (230–400
mesh). The solvents for which the Rf values are quoted are the
same that were used for any subsequent chromatography.
4.1, NCH), 4.85 and 4.96 (2 × 1H, 2 × s, ᎐CH ), 7.21–7.38 (5H,
᎐
2
m, ArH); δC (75 MHz, CDCl3) 16.92, 23.13, 30.04, 44.14, 62.62,
114.17, 127.39, 128.43, 128.47, 136.59, 143.13, 175.11; m/z(%)
216 (M ϩ 1ϩ, 15.7), 215 (Mϩ, 88.2), 174 (28.3), 146 (29.0), 91
(100.0).
(S)-(؉)-5-Isopropenylpyrrolidin-2-one 1
Sodium (1.45 g, 63.0 mmol) was cautiously added in small
pieces to a stirred solution of (S)-(ϩ)-1-benzyl-5-isopropenyl-
pyrrolidin-2-one (2.6 g, 12.1 mmol) in liquid ammonia (100 ml).
Initially, the blue colour around the sodium discharged but per-
sisted after 30 minutes. The ammonia was allowed to evaporate
over 4 hours. Methanol (30 ml) was cautiously added, followed
by concentration under reduced pressure. The residue was
extracted with dichloromethane (2 × 150 ml), washed with
water (3 × 60 ml), dried over magnesium sulfate and concen-
trated. Purification by flash chromatography (4:1 ether–
petroleum ether) gave (S)-(ϩ)-5-isopropenylpyrrolidin-2-one
(1, 1.1 g, 74%) as a lightly coloured solid, mp 49–50 ЊC. Vacuum
distillation bp 125 ЊC (0.5 mmHg) gave 1 which solidified on
cooling as white platelets, mp 49–50 ЊC; [α]D = ϩ0.6 (c 0.81,
CHCl3) (C7H11NO requires: C, 67.2; H, 8.9; N, 11.2%. Found:
C, 67.1; H, 8.9; N, 11.1%); νmax (KBr)/cmϪ1 3400, 1701, 1455;
(S)-(؉)-1-Benzyl-5-(1-hydroxy-1-methylethyl)pyrrolidin-2-one
Methyl iodide (24.4 g, 170.4 mmol) in ether (50 ml) was added
dropwise over 30 minutes to a suspension of magnesium (4.1 g,
170.4 mmol) in ether (100 ml), with ice cooling. When the initial
vigorous reaction had subsided, (S)-(ϩ)-1-benzyl-5-ethoxy-
carbonylpyrrolidin-2-one (12.03 g, 48.7 mmol)18 in ether (200
ml) was added dropwise over 40 minutes (the addition was such
as to maintain a steady reflux). The resulting mixture was
mechanically stirred at room temperature for 3 hours. Saturated
ammonium chloride (100 ml) was added dropwise, followed by
extraction with ether (3 × 100 ml). The combined ether frac-
tions were dried over magnesium sulfate and concentrated
under reduced pressure. Purification by flash chromatography
(60% ethyl acetate–hexane) gave (S)-(ϩ)-1-benzyl-5-(1-
hydroxy-1-methylethyl)pyrrolidin-2-one (9.5 g, 83.7%) as a
colourless oil, Rf 0.34 (C14H19NO2 requires: C, 72.1; H, 8.2; N,
6.0%. Found: C, 71.8; H, 8.5; N, 6.0%); [α]D = ϩ131.7 (c 2.81,
CHCl3); νmax (KBr)/cmϪ1 3395, 3080, 3024, 1659, 1581, 1490,
1445, 1418; δH (300 MHz, CDCl3) 1.16 (3H, s, CCH3CH3OH),
1.21 (3H, s, CCH3CH3OH), 1.55 (1H, br, OH), 1.73 (1H, ddt,
J 14.2, 9.7, 3.9, NCHCHH), 2.0 (1H, m, NCHCHH), 2.38 (1H,
ddd, J 16.9, 10.0, 5.2, NCOCHH), 2.55 (1H, ddd, J 17.1, 9.8,
7.1, NCOCHH), 3.34 (1H, dd, J 9.1, 3.5, NCH), 4.53 and 5.21
(2 × 1H, 2 × d, J 14.7, NCH2Ph), 7.24–7.35 (5H, m, ArH);
δC (75 MHz, CDCl3) 21.06, 22.99, 27.57, 29.88, 46.03, 65.00,
74.02, 126.78, 127.88, 128.07, 137.00, 176.32; m/z(%) 233 (Mϩ,
0.6), 175 (44.3), 174 (77.7), 91 (100.0).
δH (300 MHz, CDCl ), 1.73 (3H, s, ᎐CCH ), 1.88 (1H, ddt,
J 16.8, 9.9, 3.4, NCHCHH), 2.28–2.42 (3 × 1H, 3 × m,
NCHCHHCH2), 4.13 (1H, m, NCH), 4.84 and 4.94 (2 × 1H,
᎐
3
3
2 × s, ᎐CH ), 6.38 (1H, br, NH); δ (75 MHz, CDCl3) 27.29,
᎐
2
C
29.99, 56.19, 63.14, 110.80, 148.84, 179.07; m/z(%) 125 (Mϩ,
6.4), 110 (39.4), 84 (66.9), 67 (23.8), 41 (100.0).
Reaction of (S)-(؉)-5-isopropenylpyrrolidin-2-one 1 with
(R)-(؉)- and (S)-(؊)-ꢀ-methylbenzyl isocyanate
A solution of α-methylbenzyl isocyanate (11.8 mg, 0.08 mmol)
and (S)-(ϩ)-5-isopropenylpyrrolidin-2-one (10 mg, 0.08 mmol)
in toluene (2 ml) was refluxed overnight. The solvent was
removed under reduced pressure, and NMR spectra of the two
diastereoisomeric urethane derivatives were recorded. For (R)-
(ϩ)-α-methylbenzyl isocyanate adduct δH (300 MHz, CDCl3)
1.52 (3H, d, J 7.0, NCHPhCH ), 1.75 (3H, s, ᎐CCH ), 1.81
᎐
3
3
(1H, m, NCHCHH), 2.21 (1H, m, NCHCHH), 2.50 (1H, m,
NCOCHH), 2.64 (1H, m, NCOCHH), 4.65 and 4.81 (2 × 1H,
2 × s, ᎐CH ), 4.75 (1H, m, NCH), 5.05 (1H, quintet, J 6.7,
᎐
2
NHCHCH3), 7.25–7.43 (5H, m, ArH), 8.59 (1H, d, J 6.9, NH).
For (S)-(Ϫ)-α-methylbenzyl isocyanate adduct δH (300 MHz,
CDCl ) 1.53 (3H, d, J 7.0, NCHPhCH ), 1.78 (3H, s, ᎐CCH ),
᎐
3
3
3
1.80 (1H, m, NCHCHH), 2.18 (1H, m, NCHCHH), 2.40 (1H,
m, NCOCHH), 2.70 (1H, m, NCOCHH), 4.77 and 4.88
(2 × 1H, 2 × s, ᎐CH ), 4.70 (1H, m, CONCH), 5.11 (1H, quin-
᎐
2
tet, J 6.9, NHCHCH3), 7.24–7.39 (5H, m, Ar), 8.63 (1H, d,
J 7.0, NH).
(S)-(؉)-1-Benzyl-5-isopropenylpyrrolidin-2-one
Using the resonance for the vinylic protons at δ 4.65 ppm
and 4.77 ppm for each of the two diastereoisomers the two
samples independently showed a 98:2 and a 2:98 ratio of
two diastereoisomers. This translates to an ee of 96% for the
pyrrolidinone 1.
Thionyl chloride (6.0 ml, 82 mmol) was added dropwise, over 20
minutes, to a magnetically stirred solution of (S)-(ϩ)-1-benzyl-
5-(1-hydroxy-1-methylethyl)pyrrolidin-2-one (9.07 g, 38.9
mmol) in THF (250 ml), at Ϫ78 ЊC. The mixture was stirred at
this temperature for 2.5 hours before the dropwise addition of
triethylamine (95 ml, 0.66 mol) at Ϫ78 ЊC, over 30 minutes. The
solvent was then removed under reduced pressure, extracted
with dichloromethane (3 × 50 ml) and washed with water
(3 × 100 ml). Drying over magnesium sulfate and concentration
under reduced pressure, followed by vacuum distillation gave
(S)-(ϩ)-1-benzyl-5-isopropenylpyrrolidin-2-one (6.79 g, 81%)
as a colourless oil, bp 111–115 ЊC (0.001 mmHg); [α]D = ϩ195.6
(c 2.01, CHCl3) (C14H17NO requires: C, 78.1; H, 8.0; N, 6.5%.
Found: C, 78.4; H, 8.0; N, 6.8%); νmax (KBr)/cmϪ1 3057, 3024,
1685, 1647, 1600, 1581, 1491, 1451; δH (300 MHz, CDCl3) 1.63
2,3-Dibromononanoic acid 3
Dry bromine (5.8 ml, 112 mmol) was added to a stirred solution
of non-2-enoic acid (16.03 g, 102 mmol) in dry dichloro-
methane (100 ml). After the initial exothermic reaction had
subsided the mixture was stirred at room temperature over-
night. The resulting mixture was washed with 1 M sodium thio-
sulfate (2 × 25 ml) and brine (2 × 30 ml), dried over magnesium
sulfate and concentrated under reduced pressure and gave 2,3-
dibromononanoic acid (30.97 g, 96%) as a yellow oil which
solidified upon pumping, mp 32–36 ЊC. This material was used
without purification for the next stage. νmax (KBr)/cmϪ1 3600,
2950, 1712, 1461, 1424 cmϪ1; δH (300 MHz, CDCl3) 0.80 (3H,
(3H, s, ᎐CCH ), 1.73 (1H, ddd, J 17.0, 9.7, 7.1, NCHCHH),
᎐
3
2.12 (1H, m, NCHCHH), 2.49 (2 × 1H, m, NCOCH2), 3.63
and 5.07 (2 × 1H, 2 × d, J 14.5, NCH2Ph), 3.90 (1H, dd, J 8.7,
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137
1133

View Article Online
m, CH3), 1.10–1.70 (8H, 8 × m, (CH2)4CH3), 1.82 (1H, m,
CHHCHBr), 2.25 (1H, m, CHHCHBr), 4.32–4.46 (2 × 1H,
2 × m, CHBrCHBrCO2), 7.88 (1H, br, COOH); m/z(%) 318
142.16; m/z(%) 222 (M ϩ, 12.3), 220 (M ϩ, 11.9), 204
81Br 79Br
(100.0), 202 (96.0), 123 (42.3).
(M2 ϩ, 0.02), 316 (M
ϩ, 0.04), 314 (M2 ϩ, 0.03), 237
(E)-1,2-Dibromonon-2-ene 5
81Br
79Br81Br
79Br
(71.1), 235 (73.2), 255 (57.7), 109 (100.0).
Dry bromine (1.44 g, 9.0 mmol) in dry acetonitrile (5 ml) was
added dropwise over 10 minutes to a stirred suspension of
triphenylphosphine (2.36 g, 9.0 ml) in acetonitrile (15 ml), at
0 ЊC. (E)-2-Bromonon-2-en-1-ol (1.81 g, 8.14 mmol) was added
to the solution at 0 ЊC and allowed to warm to room temper-
ature, whereupon it became homogeneous. The mixture was
stirred for three hours, the acetonitrile was removed under
reduced pressure and petroleum ether (100 ml) added to the
residue. The suspension was stirred for 20 minutes, the solids
filtered and washed with a further portion of petroleum ether
(30 ml). The petroleum ether fractions were combined, dried
over magnesium sulfate and concentrated under reduced pres-
sure. Purification by flash chromatography (petroleum ether)
gave (E)-1,2-dibromonon-2-ene (1.9 g, 83%) as a colourless oil.
An analytical sample was obtained by vacuum distillation,
bp 89–92 ЊC (10 mmHg), Rf 0.7 (hexane) (C9H16Br2 requires:
C, 38.1; H, 5.7%. Found: C, 38.2, H, 5.9%); νmax (KBr)/cmϪ1
1638, 1626, 1611, 1466, 1452; δH (300 MHz, CDCl3) 0.89 (3H,
t, J 6.5, CH3), 1.50 (8H, overlapping m, (CH2)4CH3), 2.10
(E/Z)-2-Bromonon-2-enoic acid 4
A solution of 1 M potassium hydroxide (150 ml) was added to
2,3-dibromononanoic acid (21.50 g, 68 mmol) and this was
heated at 35–40 ЊC for 56 hours. The solution was acidified
with concentrated hydrochloric acid (18 ml, 219 mmol) and
extracted with ether (1 × 50 ml). The organic layer was washed
with brine (2 × 20 ml), dried over magnesium sulfate and con-
centrated under reduced pressure. Vacuum distillation gave
2-bromonon-2-enoic acid (11.31 g, 71%), as clear liquid, bp 90–
92 ЊC (2 mmHg) as a mixture of (E)- and (Z)-isomers ratio 5.7:1
(C9H15BrO2 requires: C, 46.0; H, 6.4%. Found: C, 45.6; H,
6.2%); νmax (KBr)/cmϪ1 3919, 3735, 1689, 1601, 1462, 1453,
1418; δH (300 MHz, CDCl3, (E)-isomer) 0.89 (3H, t, J 6.9, CH3),
1.20–1.46 (8H, overlapping m, (CH2)4CH3), 2.57 (2H, q, J 7.5,
ϩ
2
81Br
᎐CHCH ), 6.88 (1H, t, J 7.8H, CBr᎐CH); m/z(%) 236 (M
,
᎐
᎐
3.4), 234 (M ϩ, 2.9), 179 (26.9), 177 (26.4), 155 (60.6).
79Br
(2H, q, J 7.4, ᎐CHCH ), 4.25 (2H, s, CH Br), 6.05 (1H, t,
᎐
2
2
(E)-2-Bromonon-2-enoic acid methyl ester
J 7.4, ᎐CH); m/z(%) 286 (M ϩ, 7.2), 284 (M ϩ, 13.5),
᎐
2
81Br
81Br79Br
DMSO (75 ml), followed by iodomethane (5.0 ml, 80 mmol)
was added to a stirred solution of the previously prepared 2-
bromonon-2-enoic acid (5.0 g, 21.3 mmol) in potassium hydrox-
ide solution (15 ml) [2.0 g in water (15 ml)]. The clear yellow
solution became cloudy and was stirred at room temperature
for 20 hours. Water (100 ml) was added and the resulting
mixture was extracted with ether (3 × 50 ml). The combined
ethereal extracts were washed with water (3 × 30 ml), dried over
magnesium sulfate and concentrated under reduced pressure.
Purification by flash chromatography (1:99 ether–petroleum
ether) gave pure (E)-2-bromonon-2-enoic acid methyl ester
(3.18 g, 60%) as a colourless oil. (E)-isomer, Rf 0.6; (Z)-isomer,
Rf 0.5; bp 80–85 ЊC (1 mmHg) (C10H17BrO2 requires: C, 48.2, H,
6.9%. Found: C, 48.2; H, 6.6%); νmax (KBr)/cmϪ1 1729, 1647,
1619, 1452, 1432; δH (300 MHz, CDCl3) 0.88 (3H, t, J 7.0,
CH2CH3), 1.20–1.50 (8H, overlapping m, (CH2)4CH3), 2.47
79
282 (M2 Br, 11.3), 124 (11.3), 123 (100.0).
(Z)-2-Bromohex-2-enal 6
Bromine (8.16 g, 51.1 mmol) was added dropwise over two
hours to a solution of (E)-hex-2-enal (5.0 g, 51.1 mmol) in
dichloromethane (30 ml) at 0 ЊC. The temperature was always
maintained below 5 ЊC. Two hours after final addition triethyl-
amine (7.70 g, 76.2 mmol) was added dropwise to the mixture
and the resulting solution was stirred at room temperature for
24 hours. The solvent was removed under reduced pressure and
ether (35 ml) added, and this was washed with water (3 × 15 ml)
and brine (15 ml). The organic layer was dried over magnesium
sulfate and concentrated to give (Z)-2-bromohex-2-enal as a
yellow oil (9.0 g, 99% crude). The crude product was deemed
pure enough to be used for the next step. The corresponding
(E)-isomer could not be detected in the crude mix by 13C NMR
spectroscopy. νmax (KBr)/cmϪ1 2964, 2934, 1702, 668; δH (500
MHz, CDCl3) 1.01 (3H, t, J 7.4, CH3), 1.62 (2H, septet, J 7.4,
CH2CH3), 2.52 (2H, q, J 7.4, CH2CH), 7.17 (1H, t, J 7.4,
(2H, q, J 7.7, ᎐CHCH ), 3.81 (3H, s, OCH ), 6.69 (1H, t, J 7.7,
᎐
2
3
᎐CH); δ (125 MHz, CDCl ) 14.67, 23.17, 29.34, 29.47, 32.16,
᎐
C
3
32.18, 53.39, 111.04, 150.16, 163.95; m/z(%) 250 (M ϩ, 4.0),
81Br
248 (M ϩ, 5.6), 193 (15.2), 191 (13.9), 169 (96.5), 167 (88.0),
79Br
CH᎐), 9.21 (1H, s, CHO); δ (75 MHz, CDCl3) 14.20, 21.34,
᎐
C
109 (100.0).
34.34, 129.29, 156.08, 186.58; m/z(%) 177 (11.5), 97 (39.5), 67
(41.5), 43 (31.0), 39 (100.0).
(E)-2-Bromonon-2-en-1-ol
DIBAL-H 1 M (16 ml, 24 mmol) was added dropwise, over 40
minutes, to a stirred solution of (E)-2-bromonon-2-enoic acid
methyl ester (2.6 g, 10.4 mmol) in ether (80 ml), at Ϫ78 ЊC,
whilst maintaining the temperature below Ϫ65 ЊC during the
addition. The mixture was then allowed to warm to 0 ЊC slowly
over 2 hours, water (1 ml) was cautiously added dropwise, fol-
lowed by the dropwise addition of a hydrochloric acid solution
(25 ml) [concentrated acid (5 ml) in water (20 ml)]. The two-
phase mixture was stirred vigorously at room temperature
for 2 hours to dissolve the solids. The aqueous layer was
extracted with ether (2 × 30 ml) and the combined organic
extracts were washed with water (2 × 30 ml), dried over
magnesium sulfate and concentrated under reduced pressure.
Purification by vacuum distillation gave (E)-2-bromonon-2-en-
1-ol (2.1 g, 82%) as a colourless oil, bp 80–82.5 ЊC (1 mmHg)
(C9H17BrO requires: C, 49.3; H, 7.7%. Found: C, 49.6; H,
7.5%); νmax (KBr)/cmϪ1 3350, 1641, 1452; δH (300 MHz, CDCl3)
0.88 (3H, t, J 5.8, CH2CH3), 1.27–1.45 (8H, overlapping m,
(Z)-2-Bromohex-2-en-1-ol
Sodium borohydride (0.2 g, 5.3 mmol) was added in small por-
tions to a solution of (Z)-2-bromohex-2-enal (2.0 g, 11.2 mmol)
in ethanol (20 ml) and the resulting solution was stirred for
2 hours. The solvent was then removed under reduced pressure
and the residue was taken up with dichloromethane (50 ml) and
washed with water (3 × 20 ml), dried over magnesium sulfate
and concentrated. Distillation of the crude yellow oil gave
(Z)-2-bromohex-2-en-1-ol as a colourless oil (1.15 g, 56.9%), bp
48 ЊC (3 mmHg) (C6H11OBr requires: C, 40.2; H, 6.2%. Found:
C, 39.9; H, 6.3%); νmax (KBr)/cmϪ1 3341, 2961, 2872, 1656, 684;
δH (500 MHz, CDCl3) 0.94 (3H, t, J 7.4, CH3), 1.45 (2H, sextet,
J 7.4, CH CH ), 2.18 (2H, q, J 7.4, CH CH᎐), 2.28 (1H, br s,
᎐
2
3
2
OH), 4.24 (2H, s, CH OH), 6.00 (1H, t, J 7.4, C᎐CH); δ (75
᎐
2
C
MHz, CDCl3) 14.49, 22.30, 33.55, 69.20, 127.43, 131.07; m/z(%)
180 (10.3), 178 (10.3), 99 (7.2), 81 (69.0), 79 (19.0), 57 (100.0).
(Z)-1,2-Dibromohex-2-ene 7
(CH ) CH ), 1.95 (1H, br, OH), 2.11 (2H, q, J 7.3, ᎐CHCH ),
᎐
2
4
3
2
4.30 (2H, s, CH OH), 6.02 (1H, t, J 7.8, CBr᎐CH); δ (75 MHz,
Phosphorus tribromide (0.15 ml, 1.58 mmol) was added to a
᎐
2
C
CDCl3) 14.21, 22.37, 25.14, 26.60, 28.77, 31.62, 46.67, 122.89,
solution of (Z)-2-bromohex-2-en-1-ol (0.85 g, 4.75 mmol) in
1134 J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137

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dry ether (12 ml) at Ϫ20 ЊC under an atmosphere of dry nitro-
gen. The reaction mixture was then allowed to warm to room
temperature and stirred for a further hour. The reaction was
quenched with saturated sodium carbonate (15 ml) and
extracted with ether (3 × 10 ml). The combined organic layers
were washed with brine (10 ml), dried over magnesium sulfate
and concentrated. The crude material (0.29 g, 64%) was deemed
pure enough to be used for the next step. δH (300 MHz, CDCl3)
0.79 (3H, t, J 7.3, CH3), 1.31 (2H, sextet, J 7.3, CH2CH3), 2.01
(2H, q, J 7.3, CH2CH), 4.10 (2H, s, CH2Br), 5.96 (1H, t, J 7.3,
(S)-1-[(E)-2-Bromonon-2-enyl]-5-(1-chloromethylvinyl)-
pyrrolidin-2-one
Calcium hypochlorite (790 mg, 6.7 mmol) was dissolved in
water (7 ml) and this was added to (S)-1-[(E)-2-bromonon-
2-enyl]-5-isopropenylpyrrolidin-2-one (1.85 g, 5.61 mmol), in
dichloromethane (30 ml) and the two phase solution was vigor-
ously stirred. Dry ice (10 mmol) was added in small pieces over
half an hour. The resulting mixture was stirred for 45 minutes
and saturated sodium bicarbonate (50 ml) was added. The
dichloromethane layer was separated and the aqueous layer
extracted with further dichloromethane (2 × 40 ml). The com-
bined dichloromethane extracts were dried over magnesium
sulfate and concentrated under reduced pressure. Purification
by flash chromatography (60% ether–hexane) gave (S)-1-[(E)-
2-bromonon-2-enyl]-5-(1-chloromethylvinyl)pyrrolidin-2-one
(1.26 g, 62%) as a yellow oil, Rf 0.32 (80% ether–hexane)
(C16H25BrNOCl requires: M Ϫ Brϩ, 282.154. Found: M Ϫ Brϩ,
282.153); νmax (KBr)/cmϪ1 3080, 1693, 1553, 1502, 1451, 1411,
1234; δH (300 MHz, CDCl3) 0.88 (3H, t, J 6.8, CH2CH3), 1.19–
1.38 (8H, br m, (CH2)4CH3), 1.83 (1H, m, NCHCHH), 2.03
CH᎐); δ (75 MHz, CDCl ) 14.11, 21.71, 33.96, 39.41, 122.89,
᎐
C
3
135.22.
(S)-(؉)-1-[(E)-2-Bromonon-2-enyl]-5-isopropenylpyrrolidin-2-
one 8
(S)-(ϩ)-5-Isopropenylpyrrolidin-2-one (0.30 g, 2.40 mmol) in
THF (2 ml) was added dropwise, over 10 minutes, to a suspen-
sion of 60% sodium hydride (0.46 g, 2.76 mmol) in THF (18
ml), with ice cooling. (E)-1,2-Dibromonon-2-ene (0.68 g, 2.40
mmol) was added dropwise over 15 minutes, and the resulting
mixture was stirred overnight at room temperature. The THF
was removed under reduced pressure, the remaining residue was
taken up in ether (50 ml), washed with water (2 × 40 ml),
dried over magnesium sulfate and concentrated under reduced
pressure. Purification by flash chromatography (50% ether–
petroleum ether) gave (S)-(ϩ)-1-[(E)-2-bromonon-2-enyl]-5-
isopropenylpyrrolidin-2-one (8, 0.67 g, 85%) as a colourless
oil, Rf 0.41 (50% ether–petroleum ether); [α]D = ϩ4.5 (c 1.04,
CHCl3) (C16H26BrNO requires: C, 58.5; H, 8.0; N, 4.3%. Found:
C, 58.5; H, 7.6; N, 4.2%); νmax (KBr)/cmϪ1 3070, 1697, 1646,
1553, 1501, 1452; δH (300 MHz, CDCl3) 0.88 (3H, t, J 7.3,
CH2CH3), 1.21–1.37 (8H, overlapping m, (CH2)4CH3), 1.67
(2H, m, ᎐CHCH ), 2.31–2.55 (3H, 3 × m, NCHCHHCH ),
᎐
2
2
3.69 (1H, d, J 15.0, NCHH), 4.04 (2H, s, CH2Cl), 4.31 (1H, dd,
J 8.3, 3.5, NCH), 4.65 (1H, d, J 15.0, NCHH), 5.10 and 5.39
(2 × 1H, 2 × s, ᎐CH ), 6.09 (1H, t, J 7.9, CBr᎐CH); δ (75
᎐
᎐
2
C
MHz, CDCl3) 14.13, 22.51, 25.03, 26.69, 28.94, 29.69, 30.16,
42.77, 44.72, 59.16, 116.31, 118.77, 137.72, 143.58, 175.44;
m/z(%) 365 (M
ϩ, 0.02), 363 (Mϩ, 0.06), 361 (MCl
,
ϩ
37Cl81Br
35Br79
0.05), 345 (0.45), 298 (1.0), 282 (M Ϫ Brϩ, 1.4), 265 (23.9), 264
(100.0).
(S)-(؉)-1-[(E)-2-Bromonon-2-enyl]-5-(1-hydroxymethylvinyl)-
pyrrolidin-2-one
(3H, s, ᎐CCH ), 1.81 (1H, ddd, J 14.7, 6.9, 4.4, NCHCHH),
᎐
3
(S)-(ϩ)-1-[(E)-2-Bromonon-2-enyl)-5-(1-chloromethylvinyl)-
pyrrolidin-2-one (1.19 g, 3.27 mmol) was dissolved in 25%
aqueous dioxane (35 ml) containing sodium bicarbonate
(0.65 g, 7.76 mmol) and the resulting mixture was boiled under
reflux for 4 days. The dioxane was removed under reduced
pressure and the residue was extracted with dichloromethane
(3 × 20 ml), dried over magnesium sulfate and concentrated.
Flash chromatography (100% ether) gave (S)-(ϩ)-1-[(E)-2-
bromonon-2-enyl]-5-(1-hydroxymethylvinyl)pyrrolidin-2-one
(0.89 g, 85%) as a colourless oil, Rf 0.28; [α]D = ϩ2.7 (c 0.49,
CHCl3) (C16H26BrNO2 requires: C, 55.8; H, 7.6; N, 4.1%.
Found: C, 56.3; H, 7.6; N, 4.0%); νmax (KBr)/cmϪ1 3406, 1671,
1553, 1451, 1432, 1415; δH (300 MHz, CDCl3) 0.88 (3H, t,
J 6.7, CH2CH3), 1.21–1.39 (8H, br m, (CH2)4CH3), 1.89 (1H,
ddt, J 16.4, 9.9, 3.5, NCHCHH), 1.96–2.12 (2 × 1H, m,
2.03–2.08 (2 × 1H, 2 × m, ᎐CHCH ), 2.24 (1H, ddd, J 13.9, 8.7,
4.6, NCHCHH), 2.43–2.49 (2 × 1H, 2 × m, OCCH2), 3.62 and
4.62 (2 × 1H, 2 × d, J 14.8, NCHHCBr), 4.10 (1H, dd, J 8.7,
᎐
2
4.3, NCH), 4.85 and 4.94 (2 × 1H, 2 × s, ᎐CH ), 6.06 (1H, t,
᎐
2
J 7.0, CBr᎐CH); δ (75 MHz, CDCl3) 14.03, 17.56, 22.53,
᎐
C
23.51, 28.75, 29.06, 29.72, 29.84, 31.58, 42.62, 62.37, 113.39,
119.18, 137.35, 143.32, 175.38; m/z(%) 329 (M ϩ, 0.5), 327
81Br
(M ϩ, 0.5), 248 (100.0), 247 (24.2), 138 (22.1).
79Br
(S)-(؉)-1-[(Z)-2-Bromohex-2-enyl]-5-isopropenylpyrrolidin-2-
one 18
Sodium hydride (previously washed with hexane) (53 mg, 2.20
mmol) was carefully added to a solution of (S)-(ϩ)-5-iso-
propenylpyrrolidin-2-one (0.25 g, 1.99 mmol) in dry THF (10
ml) at 0 ЊC. When hydrogen evolution ceased, (Z)-1,2-dibromo-
hex-2-ene (0.58 g, 2.40 mmol) was added dropwise. The cold
bath was removed and the reaction stirred at room temperature
overnight. The solvent was removed under reduced pressure
and the residue taken up with ether (10 ml), washed with water
(2 × 4 ml) and brine (4 ml). The aqueous layers were washed
with ether (5 ml). The combined ethereal layers were dried
over magnesium sulfate and concentrated. Purification by flash
chromatography (ether) gave (S)-(ϩ)-1-[(Z)-2-bromohex-2-
enyl]-5-isopropenylpyrrolidin-2-one as a colourless oil (0.21 g,
37%). Rf 0.35; [α]D = ϩ146.3 (c 4.0, CHCl3) (C13H20BrNO
requires: Mϩ, 285.073. Found: Mϩ, 285.073); νmax (KBr)/cmϪ1
3078, 2961, 2872, 1701, 1414, 903, 611; δH (300 MHz, CDCl3)
0.93 (3H, t, J 7.3, CH2CH3), 1.43 (2H, sextet, J 7.3, CH2CH3),
᎐CHCH ), 2.26–2.55 (3H, 3 × m, NCHCHHCH ), 3.71 (1H, d,
᎐
2
2
J 15.0, NCHH), 4.12 (2H, s, CH2OH), 4.22 (1H, dd, J 8.7, 3.8,
NCH), 4.62 (1H, d, J 15.0, NCHH), 4.98 and 5.29 (2 × 1H,
2 × s, ᎐CH ), 6.07 (1H, t, J 7.7, CBr᎐CH); δ (75 MHz, CDCl )
᎐
᎐
2
C
3
13.97, 22.45, 24.79, 28.66, 28.99, 29.56, 29.64, 31.51, 42.76,
59.42, 62.77, 112.16, 118.86, 137.55, 146.94, 175.70; m/z(%)
345 (M ϩ, 0.4), 343 (M ϩ, 0.4), 298 (1.0), 282 (1.3), 264
81Br
79Br
(100.0).
(S)-(؉)-2-{1-[(E)-2-Bromonon-2-enyl]-5-oxopyrrolidin-2-
yl}propenal 15
A mixture of (S)-(ϩ)-1-[(E)-2-bromonon-2-enyl]-5-(1-hydroxy-
methylvinyl)pyrrolidin-2-one (60 mg, 0.17 mmol), N-methyl-
morpholine N-oxide (45.9 mg, 0.46 mmol) and crushed
activated molecular sieves (40 mg), in dichloromethane (1.5 ml)
was cooled to 0 ЊC. Tetrapropylammonium perruthenate (10.9
mg, 0.03 mmol) was added and the mixture was allowed to
reach room temperature and stirred for a further 24 hours. The
reaction mixture was purified directly by flash chromato-
graphy (100% chloroform) and gave (S)-(ϩ)-2-{1-[(E)-2-bromo-
non-2-enyl]-5-oxopyrrolidin-2-yl}propenal (50 mg, 85%) as a
1.65 (3H, s, ᎐CCH ), 1.76–1.86 (1H, m, NCOCH CHH),
᎐
3
2
2.12–2.29 (3H, m, NCOCH CHH and ᎐CCHCH ), 2.43–2.49
᎐
2
2
(2H, m, NCOCH2), 3.43 (1H, d, J 14.9, NCHH), 4.08 (1H, dd,
J 8.7, 4.3, CH2CH), 4.73 (1H, d, J 14.9, NCHH), 4.89 (2H, d,
J 25.4, ᎐CH ), 5.83 (1H, t, J 6.8, C᎐CHCH ); δ (75 MHz,
᎐
᎐
2
2
C
CDCl3) 14.13, 17.61, 21.95, 23.69, 30.39, 33.43, 49.19, 62.85,
114.29, 122.17, 133.45, 143.47, 175.71; m/z(%) 286 (Mϩ, 13.5),
206 (100.0), 190 (5.4), 138 (46.8).
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137
1135

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heavy colourless oil, Rf 0.19; [α]D = ϩ2.9 (c 0.40, CHCl3)
(C16H24NO2Br requires: Mϩ, 341.099. Found: Mϩ, 341.100);
νmax (KBr)/cmϪ1 1684, 1553, 1534, 1501, 1452, 1410, 1277;
δH (300 MHz, CDCl3) 0.88 (3H, t, J 6.9, CH3), 1.15–1.38 (8H,
br m, (CH2)4CH3), 1.72 (1H, ddt, J 13.2, 9.8, 3.7, NCHCHH),
δ 5.47 ppm gave a 6.8% NOE at δ 3.97 ppm; δC (75 MHz,
CDCl3) 14.5, 16.91, 21.20, 22.60, 27.91, 28.92, 29.34, 29.60,
30.39, 31.67, 46.21, 103.71, 127.28, 127.39, 131.71, 173.64;
m/z(%) 249 (M ϩ 2ϩ, 8.5), 247 (Mϩ, 1.3), 233 (M Ϫ 14ϩ, 26.2),
163 (41.6), 148 (30.9), 43 (100.0).
1.90–2.05 (2H, m, ᎐CHCH ), 2.30–2.47 (3H, 3 × m, NCHCH-
᎐
2
HCH2), 3.62 (1H, d, J 15.0, NCHH), 4.62–4.71 (2 × 1H, 2 × m,
(S)-(؉)-6-(E)-Heptylidene-8-methylenehexahydroindolizin-
3(2H)-one 11. [α]D = ϩ0.5 (c 2.1, CHCl3) (C16H25NO requires:
Mϩ, 247.194. Found: Mϩ, 247.195); νmax (KBr)/cmϪ1 2926,
2853, 1589, 1483, 1458, 1432; δH (500 MHz, CDCl3) 0.88 (3H, t,
J 6.9, CH2CH3), 1.22–1.39 (8H, br m, CH3(CH2)4), 1.98–2.04
(3H, 3 × m, NCHCHH and ᎐CHCH ), 2.26 (1H, m, NCH-
NCHH and NCH), 6.06 (1H, t, J 7.7, CBr᎐CH), 6.20 and 6.22
᎐
(2 × 1H, 2 × s, C᎐CH ), 9.66 (1H, s, CHO); δ (125 MHz,
᎐
2
C
CDCl3) 14.72, 23.18, 26.16, 29.41, 29.67, 30.39, 32.22, 43.68,
55.17, 119.01, 133.88, 138.60, 149.16, 176.35, 193.59; m/z(%)
343 (M ϩ, 0.2), 341 (M ϩ, 0.2), 328 (0.2), 325 (0.3), 288
81Br
79Br
᎐
2
(0.7), 286 (1.0), 262 (100.0), 206 (2.3).
CHH), 2.40 (2 × 1H, 2 × m, NCOCH2), 2.90 and 2.95 (2 × 1H,
2 × d, J 13.9, ᎐C–CH –C᎐), 3.45 (1H, d, J 14.3, NCHH), 4.09
᎐
᎐
2
Palladium catalysed cyclisation reactions
(1H, m, NCH), 4.43 (1H, d, J 14.3, NCHH), 4.81 and 4.92
(2 × 1H, 2 × s, ᎐CH ), 5.37 (1H, t, J 7.6, ᎐CHCH ); saturation
᎐
᎐
2
2
Standard Heck conditions. Potassium carbonate (250 mg, 1.8
mmol) was added to a solution of (S)-(ϩ)-1-[(E)-2-bromonon-
2-enyl]-5-isopropenylpyrrolidin-2-one (502 mg, 1.52 mmol),
palladium acetate (36 mg, 0.16 mmol) and triphenylphosphine
(77 mg, 0.30 mmol) in acetonitrile 25 ml under a nitrogen
atmosphere and the mixture was boiled under reflux for 1 h.
The solvent was removed under reduced pressure, water (10 ml)
added and the product was extracted with dichloromethane
(2 × 20 ml), dried over magnesium sulfate and concentrated
under reduced pressure. The ratio of the isomers 9, 10 and 11
was determined by integrating the triplets at δ 5.24 ppm, 5.47
ppm and 5.37 ppm respectively in the proton NMR spectrum.
Flash chromatography gave a mixture of the three isomers (222
mg, 59% combined yield). The individual components of the
mixture were separated by multiple elution (× 14) preparative
TLC using ether–petroleum ether 9:1 as solvent and cutting
the top and bottom of bands and discarding the middle. This
eventually gave compounds 9–11 pure but the recovery in all
cases was very poor.
at δ 5.37 ppm gave a 5.0% NOE enhancement to multiplet at
δ 3.45 ppm; δC (125 MHz, CDCl3) 14.77, 23.18, 23.66, 27.70,
28.46, 29.56, 30.03, 31.53, 35.84, 47.65, 60.12, 108.94, 126.83,
127.15, 145.29, 173.32; m/z(%) 247 (Mϩ, 77.5), 232 (13.9), 176
(100.0), 162 (77.2), 148 (42.2), 41 (66.4).
5a-(E)-Hept-1-enyl-1a-methylhexahydro-4a-azacyclopropa-
[a]pentalen-4-one 12. Yellow oil, [α]D = ϩ1.5 (c 0.55, CHCl3)
(C16H25NO requires: Mϩ 247.194. Found: Mϩ 247.193); νmax
(KBr)/cmϪ1 1694, 1453, 1403, 1293, 1262; δH (500 MHz, CDCl3)
0.46 and 0.56 (2 × 1H, 2 × d, J 5.9, cyclopropane CH2), 0.87
(3H, t, J 6.9, CH2CH3), 1.09 (3H, s, CH3), 1.22–1.31 (6H, 6 × m,
CH3(CH2)3), 1.74 (1H, m, NCOCH2CHH), 2.03 (2H, q, J 6.9,
CHCH2), 2.18 (1H, m, NCOCH2CHH), 2.38 (1H, ddd, J 2.1,
10.0, 16.9, NCOCHH), 2.62 (1H, m, NCOCHH), 3.11 and 3.72
(2 × 1H, 2 × d, J 11.4, NCH2), 3.93 (1H, t, J 7.2, NCHCH2),
5.32 (1H, d, J 15.5, CH᎐CHCH ), 5.43 (1H, dt, J 15.5, 6.6,
᎐
2
CH᎐CHCH ); saturation at δ 1.09 ppm gave NOE enhance-
᎐
2
ments at δ 3.93 ppm of 7.6% and at δ 5.32 ppm of 6.1%; δC (75
MHz, CDCl3) 14.58, 14.71, 17.19, 23.14, 24.14, 29.87, 33.40,
33.84, 35.08, 28.24, 67.29, 127.48, 132.34, 175.89; m/z(%)
248 (M ϩ 1, 11.41), 247 (Mϩ, 63.09), 232 (10.1), 190 (32.2),
107 (45.6), 93 (100).
Jeffery conditions. Same as above except that tetraethyl-
ammonium chloride (252 mg, 1.53 mmol) was added and 24 h
at room temperature were required for consumption of vinyl
bromide starting materials.
Cyclisation of (S)-(؉)-2-{1-[(E)-2-bromonon-2-enyl]-5-oxo-
pyrrolidin-2-yl}propenal 15
Thallium acetate conditions. Same as standard Heck condi-
tions with substitution of thallium acetate (370 mg, 1.4 mmol)
for potassium carbonate. 48 h were required for consumption
of vinyl bromide starting material.
A solution of (S)-2-{1-[(E)-2-bromonon-2-enyl]-5-oxopyrrol-
idin-2-yl}propenal (40 mg, 0.122 mmol), potassium carbonate
(1.83 mg, 0.013 mmol), palladium() acetate (3 mg, 0.012
mmol) and triphenylphosphine (6.4 mg, 0.024 mmol) in
anhydrous acetonitrile (2 ml) was stirred at room temperature
for 24 hours. The crude proton NMR spectrum suggested
incomplete reaction so the solution was refluxed for a further 30
minutes. The acetonitrile was removed under reduced pressure
and the resulting residue extracted with ether (2 × 30 ml),
dried over magnesium sulfate and concentrated under
reduced pressure. Flash chromatography (solvent diethyl
ether) gave 16 and 17 as an inseparable mixture (25 mg,
59%). The products 16 and 17 were separated by multiple
elution TLC (100% ether).
(S)-(؉)-6-(E)-Heptylidene-8-methyl-1,5,6,8a-tetrahydro-
indolizin-3(2H)-one 9. [α]D = ϩ0.7 (c 1.1, CHCl3) (C16H25NO
requires: Mϩ, 247.194. Found: Mϩ, 247.193); νmax (KBr)/cmϪ1
1689, 1590, 1535, 1452, 1431, 1414; δH (500 MHz, CDCl3) 0.88
(3H, t, J 6.6, CH2CH3), 1.23–1.38 (8H, 8 × m, (CH2)4CH3),
1.62 (1H, m, NCHCHH), 1.79 (3H, s, ᎐CCH ), 2.10 (2H,
᎐
3
q, J 7.3, ᎐CHCH ), 2.32 (1H, m, NCHCHH), 2.45 (2 × 1H, m,
᎐
2
NCOCH2), 3.47 (1H, d, J 15.0, NCHH), 4.09 (1H, m,
NCH), 4.49 (1H, d, J 14.8, NCHH), 5.24 (1H, t, J 7.7,
C᎐CHCH ), 6.21 (1H, s, MeC᎐CH); saturation of signal at
᎐
᎐
2
δ 6.21 gave a 5.5% NOE at δ 4.09 ppm; δC (125 MHz, CDCl3)
14.77, 19.28, 23.28, 26.22, 27.45, 29.64, 30.26, 32.34, 32.38,
43.54, 59.24, 119.79, 127.04, 128.40, 136.60, 173.24; m/z(%) 247
(Mϩ, 78.5), 232 (100.0), 176 (68.5), 162 (43.1), 148 (43.6).
(S)-6-(E)-Heptylidene-3-oxo-1,2,3,5,6,7-hexahydroindolizine-
8-carbaldehyde 16. The title product was obtained pure from
multiple elution preparative TLC as a yellow oil, Rf 0.21
(C16H23NO2 requires: Mϩ, 261.173. Found: Mϩ, 261.173); νmax
(KBr)/cmϪ1 1673, 1661, 1548, 1452, 1413; δH (300 MHz, CDCl3)
0.88 (3H, t, J 6.7, CH2CH3), 1.16–1.43 (8H, br m, (CH2)4CH3),
6-(E)-Heptylidene-8-methyl-1,5,6,7-tetrahydroindolizin-
3(2H)-one 10. (C16H25NO requires: C, 77.7; H, 10.2; N, 5.7%.
Found: C, 77.2; H, 10.3; N, 5.6%) (Found: M Ϫ CH2ϩ, 233.178.
C15H23NO requires: M Ϫ CH2ϩ, 233.178); νmax (KBr)/cmϪ1
1679, 1591, 1451, 1409, 1374, 1257; δH (300 MHz, CDCl3) 0.88
(3H, t, J 6.8, CH2CH3), 1.22–1.40 (8H, overlapping m, (CH2)4-
2.06 (2H, q, J 7.1, ᎐CHCH ), 2.64–2.68 (2H, m, NCOCH CH ),
᎐
2
2
2
3.06 (2H, s, ᎐C–CH –C᎐), 3.22 (2H, m, NCOCH ), 4.08 (2H, s,
᎐
᎐
2
2
NCH ), 5.57 (1H, t, J 6.9, ᎐CHCH ), 9.74 (1H, s, CHO); satur-
᎐
2
2
CH ), 1.65 (3H, s, ᎐CCH ), 2.03 (2H, m, ᎐CHCH ), 2.48 and
ation at δ 5.57 ppm gave an NOE enhancement of 6.8% at
δ 4.08 ppm; δC (75 MHz, CDCl3) 14.72, 21.83, 23.36, 25.67,
28.43, 29.57, 30.24, 31.08, 32.37, 45.68, 105.39, 127.28, 127.40,
᎐
᎐
3
3
2
2.58 (2 × 2H, 2 × m, NCOCH CH ), 2.72 (2H, s, ᎐C–CH –C᎐),
᎐
᎐
2
2
2
3.97 (2H, s, NCH ), 5.47 (1H, t, J 7.1, ᎐CHCH ); saturation at
᎐
2
2
1136
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137

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131.84, 174.02, 201.57; m/z(%) 261 (Mϩ, 24.8), 246 (100.0), 232
(12.7), 176 (41.9).
2 J. W. Daly and C. W. Myers, Science, 1967, 156, 970.
3 T. Tokuyama, J. W. Daly and R. J. Highet, Tetrahedron, 1984, 40,
1183.
4 J. P. Michael Nat. Prod. Rep., 1997, 14, 21; P. Jain, H. M. Garraffo,
T. F. Spande, H. J. C. Yeh and J. W. Daly, J. Nat. Prod., 1995, 58,
100.
5 H. M. Garraffo, J. Caceres, J. W. Daly and T. F. Spande, J. Nat.
Prod., 1993, 56, 1016
6 J. W. Daly, personal communication, November 1994.
7 L. E. Overman and A. S. Franklin, Chem. Rev., 1996, 96, 505.
8 J. W. Daly, E. McNeal, F. Gusovsky, F. Ito and L. E. Overman,
J. Med. Chem., 1988, 31, 477.
9 L. E. Overman and K. L. Bell, J. Am. Chem. Soc., 1981, 103,
1851; L. E. Overman and M. J. Sharp, Tetrahedron Lett., 1988, 29,
901.
6-(E)-Heptylidene-3-oxo-1,2,3,5,6,8a-hexahydroindolizine-8-
carbaldehyde 17. Again the title product was obtained pure
from multiple elution preparative TLC as a yellow oil Rf
0.24 (C16H23NO2 requires: Mϩ, 261.189. Found: Mϩ, 261.191);
δH (500 MHz, CDCl3) 0.89 (3H, t, J 6.7, CH2CH3), 1.33 (8H, br
m, (CH2)4CH3), 1.57 (1H, ddt, J 16.9, 9.7, 3.5, NCHCHH),
2.12 (2H, q, ᎐CHCH ), 2.30 (1H, m, NCHCHH), 2.48 (2H, m,
᎐
2
NCOCH2), 3.46 (1H, d, J 14.8, NCHH), 4.23 (1H, m, NCH),
4.71 (1H, d, J 15.1, NCHH), 5.89 (1H, t, J 7.6, ᎐CHCH ), 7.34
᎐
2
(1H, s, ᎐CH), 9.53 (1H, s, CHO); saturation at δ 5.89 ppm gave
᎐
a 6.3% NOE at δ 4.71 ppm; m/z(%) 261 (Mϩ, 2.3), 246 (87.4),
10 L. E. Overman and S. W. Goldstein, J. Am. Chem. Soc., 1984, 106,
5360; D. N. A. Fox, D. Lathbury, M. F. Mahon, K. C. Molloy and
T. Gallagher, J. Am. Chem. Soc., 1991, 113, 2652; A. G. M. Barrett
and F. Damiani, J. Org. Chem., 1999, 64, 1410.
176 (21.4).
(S)-(؊)-6-(Z)-Butylidene-8-methyl-1,5,6,8a-tetrahydro-
indolizin-3(2H)-one 19. Potassium carbonate (97 mg, 0.70
mmol) was added to a solution of (S)-1-[(Z)-2-bromohex-2-
enyl]-5-isopropenylpyrrolidin-2-one (200 mg, 0.70 mmol), pal-
ladium acetate (15.7 mg, 0.07 mmol) and triphenylphosphine
(37 mg, 0.14 mmol) in dry acetonitile (15 ml) under a nitrogen
atmosphere and the mixture was refluxed overnight. The
solvent was removed under reduced pressure and the residue
extracted with ether (3 × 10 ml). The combined organic layers
were dried over magnesium sulfate and concentrated to give a
brown oil. Purification by flash chromatography column (ether)
11 S. Aoyagi, T. C. Wang and C. Kibayashi, J. Am. Chem. Soc., 1993,
115, 11393; D. Montgomery, K. Reynolds and P. J. Stevenson,
J. Chem. Soc., Chem. Commun., 1993, 363.
12 B. M. Trost and T. S. Scanlan, J. Am. Chem. Soc., 1989, 111, 4988;
H. McAlonan, D. Montgomery and P. J. Stevenson, Tetrahedron
Lett., 1996, 37, 7151; S. Aoyagi, Y. Hasegawa, S. Hirashima and
C. Kibayashi, Tetrahedron Lett., 1998, 39, 2149.
13 X. Q. Tang and J. Montgomery, J. Am. Chem. Soc., 1999, 121, 6098;
S. Okamoto, M. Iwakubo, K. Kobayashi and F. Sato, J. Am. Chem.
Soc., 1997, 119, 6984.
14 H. Rapoport, J. S. Petersen and F. Gregor, J. Am. Chem. Soc., 1984,
106, 4539.
15 W. H. Pirkle, M. R. Robertson and M. Hyun, J. Org. Chem., 1984,
49, 2433.
16 T. C. James, J. Chem. Soc., 1910, 1565.
17 R. J. Abraham, J. Fisher and P. Loftus, Introduction to NMR
Spectroscopy, Wiley, Chichester, 1988, 18.
18 R. Grigg, V. Santhakumar, V. Sridharan, P. Stevenson, A. Teasdale,
M. Thornton-Pett and T. Workun, Tetrahedron, 1991, 47, 9703.
19 J. H. Rigby, J. Am. Chem. Soc., 1995, 117, 7834; T. Jeffrey,
Tetrahedron Lett., 1991, 32, 2121.
20 R. Grigg and V. Sridharan, Tetrahedron Lett., 1993, 34, 7471;
R. Grigg, V. Loganathan, S. Sukirthalingam and V. Sridharan,
Tetrahedron Lett., 1990, 31, 6573.
21 V. H. Rawal and C. Michoud, J. Org. Chem., 1993, 58, 5583.
22 Z. Owczarczyk, F. Lumaty, E. J. Vawter and E. Negishi, J. Am.
Chem. Soc., 1992, 114, 10091.
23 A. L. J. Beckwith and D. M. O’Shea, Tetrahedron Lett., 1986, 27,
4525; G. Stork and R. Mook, Tetrahedron Lett., 1986, 27, 4529;
D. Critch, J. Hwang and H. Liu, Tetrahedron Lett., 1996, 37, 3105.
24 A. Brown, R. Grigg, T. Rasvishankar and M. Thorton-Pett,
Tetrahedron Lett., 1994, 35, 2753; L. E. Overman, M. M. Abelman,
D. J. Kucera, V. D. Tran and D. J. Ricca, Pure Appl. Chem., 1992,
64, 1813.
25 J. Wolinsky and S. G. Hedge, J. Org. Chem., 1982, 47, 3148.
26 B. Bachman, J. Am. Chem. Soc., 1933, 55, 4279.
27 C. E. Fuller and D. G. Walker, J. Org. Chem., 1991, 56, 4066.
28 M. J. Rozema, C. Eisenberg, H. Lutjens, R. Ostwald, K. Belyk and
P. Knochel, Tetrahedron Lett., 1993, 34, 3115.
gave
(S)-(Ϫ)-6-(Z)-butylidene-8-methyl-1,5,6,8a-tetrahydro-
indolizin-3(2H)-one as a colourless oil (80 mg, 56%), Rf 0.20;
[α]D = Ϫ10.4 (c 4.3, CHCl3) (C13H19NO requires: Mϩ 205.147.
Found: Mϩ 205.146); νmax (KBr)/cmϪ1 2961, 1694, 1419, 1303,
896; δH (500 MHz, CDCl3) 0.91 (3H, t, J 7.4, CH3CH2), 1.36–
1.44 (2H, m, CH3CH2), 1.62 (1H, tt, J 11.8, 9.7, COCH2CHH),
1.75 (3H, s, ᎐CCH ), 2.09–2.16 (2 × 1H, 2 × m, C᎐CHCH ),
᎐
᎐
3
2
2.30 (1H, m, COCH CHH), 2.38–2.51 (2 × 1H, m, C᎐CHCH ),
᎐
2
2
3.35 (1 H, d, J 16.0, NCHH), 4.09 (1 H, t, J 8.2, NCH), 4.90
(1 H, d, J 16.0, NCHH), 5.30 (1 H, t, J 7.44, ᎐CCHCH ), 5.88
᎐
2
(1 H, s, CH C᎐CH); saturation at δ 5.88 ppm gave a 4.7% NOE
᎐
3
at δ 5.30 ppm; δC (125 MHz, CDCl3) 14.20, 18.42, 23.00, 25.76,
30.00, 32.04, 38.32, 58.34, 125.43, 128.19, 129.99, 133.64,
175.35; m/z(%) 205 (Mϩ, 82.5), 190 (100), 176 (43.1), 162 (12.5),
148 (29.6).
Acknowledgements
We would like to thank the Department of Education, N.
Ireland D.E.N.I. for studentships (D. M. and H. McA.),
European Social Fund ESF and Queens University (S. F.) for
support.
References
1 J. W. Daly, H. M. Garraffo and T. F. Spande, in The Alkaloids,
ed. G. A. Cordell, Academic Press, New York, 1993, vol. 43, p. 185.
Paper a909774k
J. Chem. Soc., Perkin Trans. 1, 2000, 1129–1137
1137

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