Total synthesis of (±)-rhazinal, an alkaloidal spindle toxin from Kopsia teoi

Article abstract of DOI:10.1039/b209992f

The title alkaloid I and its B-nor-congener 3, both of which display potent and unusual anti-mitotic properties, have been synthesized in racemic form and characterised by single-crystal X-ray analysis.

Full text of DOI:10.1039/b209992f

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Total synthesis of ( )-rhazinal, an alkaloidal spindle toxin from
Kopsia teoi
Martin G. Banwell,*a Alison J. Edwards,a Katrina A. Jolliffe,a,b Jason A. Smith,a Ernest Hamelc
and Pascal Verdier-Pinardc
a Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra, ACT 0200, Australia. E-mail: mgb@rsc.anu.edu.au
b School of Chemistry, University of Sydney, NSW 2006, Australia
c Screening Technologies Branch, Developmental Therapeutics Program,
Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick,
National Institutes of Health, Frederick, Maryland 21702, USA
Received 14th October 2002, Accepted 11th November 2002
First published as an Advance Article on the web 19th December 2002
The title alkaloid 1 and its B-nor-congener 3, both of which display potent and unusual anti-mitotic properties,
have been synthesized in racemic form and characterised by single-crystal X-ray analysis.
tethered acrylate thereby allowing for construction of the
Introduction
D-ring of targets 1 and 3. To the best of our knowledge the
present work provides the first examples of such a process,20
which we believe holds considerable potential for the con-
struction of a wide-range of other annulated pyrroles.
In 1998 Kam and co-workers reported on the isolation of the
alkaloid (Ϫ)-rhazinal (1) from the stem extracts of a Malayan
Kopsia species.1 The compound had also been prepared by
Vilsmeier–Haack formylation2 of the closely related alkaloid
(Ϫ)-rhazinilam (2), first isolated in 1965 from Melodinus aus-
tralia,3 then again in 1970 from Rhazya stricta (Apocynaceae)4
and most recently (1987) from the Malaysian plant Kopsia
singapurensis (Ridlay).5 Compound 2, at least, is an artefact
of the isolation process, and the natural precursor is 5,21-
dihydrorhazinilam.6 Rhazinilam, which can be prepared from
the natural product vincadifformine,7,8 has been the subject
of three successful total syntheses, the first by Smith7,8 in
1973 then by Sames (2000)9 and Magnus (2001).10 In contrast,
rhazinal has not, hitherto, been prepared by total synthesis.
Results and discussion
(a) Preliminary synthetic approaches involving cyclopropane
chemistry
In broad terms, our approach to rhazinal was to involve a late
stage lactamisation reaction so as to establish the B-ring and
with the early chemistry focused on exploiting regioselective
electrophilic substitution reactions that can be carried out on
pyrrole.21 The initial version of this strategy (Fig. 1) was aimed
at engaging gem-dibromocyclopropane 4 in an electrocyclic
ring-opening reaction in the expectation that the resulting
π-allyl cation would be captured by C2 of the tethered pyrrole
so as to form bromoalkene 5.22 Reaction of this latter com-
pound with an excess of strong base should effect dehydro-
bromination then deprotonation to give the corresponding
alkynyl anion which could be captured with methyl chloro-
formate to deliver propiolate 6. Hydrogenation of this last
compound should then provide the requisite substrate for the
foreshadowed lactamisation process which would deliver target
( )-1.
The preliminary steps associated with attempts to implement
such an approach are shown in Scheme 1. Thus, the synthesis
of the potential cyclisation substrate, compound 4 (X = NO2,
Y = CO2Me), started with Michael addition of the anion
derived from nitropropane (7) to methyl acrylate (8) thus
forming conjugate 923 (65%). Subjection of the last compound
to a Nef reaction using Oxone24 then afforded the correspond-
ing ketone 1025 (95%). Wittig methylenation of compound 10
afforded the alkene 1126 (30%) which was immediately reduced
to the corresponding alcohol 1227 (57%) using LiAlH4. The
The above-mentioned conversion 2
1 was undertaken as
part of an extensive analoguing program carried out around
rhazinilam after it was reported that this alkaloid mimics the
effects of both vinblastine and Taxol by inducing a non-
reversible assembly (spiralisation) of tubulin (a vinblastine-type
effect) AND by inhibiting the cold-induced disassembly
of microtubules (a Taxol-like property).2,5,11 In an even more
striking similarity to Taxol, rhazinilam has the ability to
induce formation of asters in mitotic cells and microtubule
bundles in interphase cells.11 Such observations account for
the renewed interest in compound 212 and prompted the two
recently reported total syntheses9,10 as well as the production
of numerous series of structurally simpler analogues.2,13–17
As part of a continuing program18 in this laboratory directed
towards the synthesis of pyrrole-containing natural products,
we now report the first total synthesis of rhazinal (1) and also
provide full details of a previously communicated19 and related
synthesis of its lower homologue ( )-B-norrhazinal (3). A key
feature associated with these syntheses is the use of an intra-
molecular Michael addition of the C2 of pyrrole to an N1-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 6 – 3 0 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Fig. 1
readily derived tosylate 13 (76%) was then subjected to dibromo-
carbene addition under phase transfer conditions and in this
manner the gem-dibromocyclopropane 14 was obtained in 70%
yield. Reaction of this last compound under solvent free con-
ditions with the sodium salt of 2-nitrophenylated pyrrole 15,7
readily derived via a Pd[0]-catalysed Ullmann cross-coupling28
of o-nitrobromobenzene with methyl 4-iodo-1H-pyrrole-2-
carboxylate,29 then afforded the target substrate 4 (X = NO2,
Y = CO2Me) (quantitative) required for examination of the
pivotal cyclisation step. In the event, all attempts, including
those involving the use of silver salts and/or the application of
heat, failed to effect electrocyclic ring-opening of cyclopropane
4 (X = NO2, Y = CO2Me) and consequent formation of target 5.
Either starting material was recovered or, under more forcing
conditions, its complete decomposition was observed. The
reluctance of this substrate to engage in the desired ring-open-
ing/nucleophilic trapping sequence is attributed to the low
degree of substitution and consequent smaller than usual
degree of strain associated with the gem-dibromocyclopropyl
moiety within compound 4 (X = NO2, Y = CO2Me).
In an attempt to persist with the sort of approach described
above, “Danishefsky-type” electrophilic cyclopropanes30
tethered to pyrroles were sought. It was hoped that these would
engage in intramolecular and homo-Michael type addition
reactions to give, in a direct fashion, analogues of compound 6
wherein the C–C triple bond had been replaced by an ethylene
unit. To such ends (Scheme 2) the readily prepared O-benzyl
derivative, 16 (70%), of alcohol 12 was subjected to reaction
with ethyl diazoacetate in the presence of rhodium diacetate
dimer31 and the resulting 2 : 1 mixture of epimeric cyclo-
propane carboxylic acid esters, 17, debenzylated under the
usual conditions to give the corresponding mixture of alcohols
18 (42% from 16). The readily derived mixture of tosylates 19
(84%) was then reacted with the potassium salt of pyrrole to
give the target compound 20 (89%), again as a 2 : 1 mixture
of epimers. Unfortunately all attempts to effect the desired
nucleophilic ring-opening of this cyclopropyl-containing
system failed. On the basis that this disappointing outcome
might be due to inadequate activation of the cyclopropyl group
within compound 20, the related and now “doubly-activated”
system 24 (Scheme 2) was sought. To these ends alkene 16 was
reacted with dimethyl diazomalonate in the presence of
rhodium diacetate dimer and the cyclopropane 21 thereby
obtained. Hydrogenolytic debenzylation of ether 21, followed
by tosylation of the resulting alcohol, 22 (45% from 20), then
afforded the tosylate 23 (67%), but this last compound failed
to react with either pyrrole or its potassium salt and thereby
Scheme 1 Reagents and conditions: (i) 0.1 M aqueous NaOH, 18 ЊC,
22 h; (ii) Oxone (2.7 mole equiv.), K2CO3, NaHCO3, aqueous acetone,
18 ЊC, 29 h; (iii) Ph3P᎐CH2 (1.1 mole equiv.), THF, 18 ЊC, 15 h; (iv)
᎐
LiAlH4 (2.2 mole equiv.), Et2O, 37 ЊC, 0.5 h; (v) p-TsCl (1.1 mole
equiv.), Et3N (1.3 mole equiv.), DMAP (cat.), CH2Cl2, 4 ЊC, 48 h;
(vi) CHBr3 (1.1 mole equiv.), 50% w/v aqueous NaOH, benzyl-
triethylammonium chloride (cat.), C6H6, 0–18 ЊC, 16 h; (vii) NaHMDS
(1 mole equiv.), THF, 65 ЊC, 16 h.
generate the pivotal substrate 24. As a consequence, this line
of investigation came to an end, and alternate means for
annulating the rhazinal D-ring to a pyrrole scaffold were
sought.
(b) Synthetic approaches involving intramolecular Michael
addition chemistry
The intermolecular Michael addition of pyrrole through C2 to
acrylates and related electrophiles represents a very effective
process,20 and the intramolecular variant, involving an N1-teth-
ered acrylate, should provide a means for constructing the
CD-ring substructure associated with target 1. Whilst such
intramolecular processes appear to be unknown, we were
encouraged to attempt implementation of this type of chem-
istry by virtue of our earlier observation32 that intramolecular
Michael addition of N1 of pyrrole to a C2-tethered acrylate is
a facile and efficient process. As a consequence the relevant
substrate, 30 (Scheme 3), was targeted and proved remarkably
easy to prepare. Thus, reaction of the potassium salt (24) of
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Scheme 2 Reagents and conditions: (i) NaH (2 mole equiv.), BnBr (1.1 mole equiv.), NaI (cat.), DMF, 18 ЊC, 18 h; (ii) N2CHCO2Et (3 mole equiv.),
Rh2(OAc)4 (0.6 mole %), CH2Cl2, 18 ЊC, 0.5 h; (iii) H2 (1 atm.), 5 % Pd on C (cat.), EtOAc–CH2Cl2–EtOH, 18 ЊC, 22 h; (iv) p-TsCl (1.1 mole
equiv.), Et3N, DMAP (cat.), CH2Cl2, 4 ЊC, 48 h; (v) pyrrole (2.0 mole equiv.), KH (2.0 mole equiv.), DMF, 18 ЊC, 1.5 h; (vi) N2C(CO2Me)2 (3.0 mole
equiv.), Rh2(OAc)4 (0.6 mole %), CH2Cl2, 18 ЊC, 0.5 h.
Scheme 3 Reagents and conditions: (i) 160 ЊC, 2 h; (ii) MeNHOMeؒHCl (1.2 mole equiv.), Et3N (1.2 mole equiv.), (2-pyridine N-oxide)disulfide (1.5
mole equiv.), Bu3P (1.5 mole equiv.), 18 ЊC, 16 h; (iii) (a) EtMgBr (3 mole equiv.), Et2O, 18 ЊC, 1 h then (b) 0.3 M aq. KHSO4 (excess), Ϫ40 ЊC, 0.1 h
then (c) NaHCO3 (excess), Ϫ40 ЊC to 18 ЊC; (iv) NaH (2 mole equiv.), (EtO)2POCH2CO2Me (2 mole equiv.), 18 ЊC, 48 h; (v) AlCl3 (5 mole equiv.),
Et2O, 18 ЊC, 5 h; (vi) POCl3 (1.1 mole equiv.), 1 : 33 v/v DMF–Et2O, 18 ЊC, 3 h; (vii) I2 (1.2 mole equiv.), AgOCOCF3 (1.2 mole equiv.), CHCl3, 18 ЊC,
4 h; (viii) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (1.5 mole equiv.), Pd(PPh3)4 (4 mole %), toluene, 2 M aq. Na2CO3 (excess),
MeOH, 80 ЊC, 1.5 h; (ix) KOBut (3.0 mole equiv.), HOBut, 18 ЊC, 3 h.
pyrrole with γ-butyrolactone (26) at 160 ЊC according to the
procedure of Li and Snyder33 afforded the previously reported
acid 27 (60–90%) which was converted into the corresponding
Weinreb amide 28 (87%) using a modified Mukaiyama amide
coupling procedure.34 Treatment of compound 28 with ethyl-
magnesium bromide followed by careful acidic work up then
gave the ketone 29 (≥ 95%), which was immediately subjected
to a Wadsworth–Emmons reaction using methyl diethylphos-
phonoacetate. The resulting 1 : 1 mixture of E- and Z-acrylates
30 (77%) could only be separated into the constituent isomers
on a small scale, so, for preparative purposes, the mixture was
used in examining the pivotal intramolecular Michael addition
reaction. Gratifyingly, on treating acrylate 30 with ca. five
molar equivalents of aluminium trichloride in diethyl ether at
18 ЊC the tetrahydroindolizine 3135 was obtained in 83% yield.
Thus far it is not clear whether both isomers of compound 30
are engaging, in a direct sense, in this cyclisation process or if
only one is with the other being isomerised to its reactive
congener under these conditions. Work aimed at clarifying this
matter and extending this type of chemistry is currently under-
way in these laboratories.
In terms of targeting rhazinal (1) it is necessary to effect the
one-carbon homologation of ester 30. However, before devising
methods for doing this it seemed appropriate to carry the latter
compound forward to ( )-B-norrhazinal (3), since this conform-
ationally more constrained analogue of the natural product
might be expected to display interesting biological properties.
To such ends, compound 31 was subjected to Vilsmeier–Haack
formylation, and this afforded, in a completely regioselective
manner, the aldehyde 32 (95%), which was reacted with iodine/
silver trifluoroacetate to give the iodinated derivative 33 (75%)
as the exclusive product of the reaction. Suzuki–Miyuara36
cross-coupling of compound 33 with 2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)benzenamine37 then gave the C4
arylated indolizidine 34 (76%). With this pivotal amino-ester in
hand, methods for effecting the foreshadowed lactamisation
reaction could be examined. In the first approach, saponific-
ation of the ester moiety within compound 34 was carried out
using ethanolic potassium hydroxide, and the carboxylate salt
thus formed was acidified with mineral acid. The resulting
amino acid was not characterised but immediately subjected to
reaction with DTMMN, the salt derived from 2-chloro-4,6-
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Scheme 4 Reagents and conditions: (i) DIBAL-H (2 mole equiv. of a 1 M solution in hexane), hexane, Ϫ78 ЊC, 0.16 h; (ii) MeSO2Cl (2 mole equiv.),
Et3N, CH2Cl2, 0 ЊC, 0.5 h; (iii) NaCN (20 mole equiv.), DMPU, 18 ЊC, 24 h; (iv) (a) KOH (26 mole equiv.), H2O–MeOH, reflux, 16 h then aq. HCl; (b)
DCC (2.2 mole equiv.), DMAP (cat.), CH2Cl2–MeOH, 18 ЊC, 3 h; (v) DMF (12 mole equiv.), POCl3 (1.1 mole equiv.), Et2O, 0 ЊC, 0.5 h; (vi) I2 (1.1
mole equiv.), AgOCOCF3 (1.1 mole equiv.), CHCl3, 0–18 ЊC, 4.5 h; (vii) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (1.65 mole
equiv.), Pd(PPh3)4 (10 mole %), toluene, 2 M aq. Na2CO3 (excess), MeOH, 80 ЊC, 1.5 h; (viii) (a) KOH (1000 mole equiv.), EtOH, 18 ЊC, 3 h then aq.
HCl; (b) EDCI (1.4 mole equiv.), DMAP (1.1 mole equiv.), CH2Cl2, 18 ЊC, 3 h.
dimethoxy-1,3,5-triazine and N-methylmorpholine,38 and in
this manner the target compound 3 (50%) was obtained. A
superior method for effecting lactamisation involved treatment
of amino-ester 34 with potassium tert-butoxide in tert-butanol,
and in this manner ( )-B-norrhazinal was formed directly and
in 74% yield (at 83% conversion). The spectral data derived
from compound 3 were in full accord with the assigned struc-
ture, but a single-crystal X-ray analysis, details of which have
been communicated previously,19 provided final confirmation.
This analysis revealed, inter alia, that the amide unit adopts an
s-cissoid conformation and that the dihedral angle between the
planes of the two aromatic rings is ca. 56Њ (which contrasts
with an angle of 96Њ reported39 for rhazinilam itself ). Details
associated with the biological evaluation of compound 3 are
provided below.
Encouraged by the successful synthesis of compound 3,
attention was now directed towards rhazinal itself. The most
effective means of achieving the necessary one-carbon homolo-
gation of ester 31 involved (Scheme 4) its LiAlH4-promoted
reduction to alcohol 35 (75%) then displacement of the readily
derived mesylate 36 (95%) with cyanide. The resulting nitrile 37
(91%) was hydrolysed to the corresponding acid, which was
then esterified with methanol in the presence of DCC–DMAP
to give the required homologous ester, 38 (63% from 37).40
Completion of the synthesis of rhazinal now involved the same
steps as employed in the preparation of congener 3. Thus,
Vilsmeier–Haack formylation provided aldehyde 39 (78%),
which was iodinated under previously described conditions
Fig. 2 A molecule of 1 derived from X-ray crystallographic data —
to give compound 40 (quantitative). Suzuki–Miyuara cross-
coupling of iodide 40 with 2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine then gave the C4 arylated
indolizidine 41 (64%). Lactamisation of this last compound via
ester hydrolysis, then EDCI–DMAP-promoted coupling of the
resulting amino acid afforded racemic rhazinal [( )-1] in 68%
yield. The 1H and 13C NMR spectra derived from this material
matched perfectly with those reported1 for the natural product,
and final confirmation of structure followed from a single-
crystal X-ray analysis (see Fig. 2 and Experimental). As
expected, this analysis reveals that, as with congener 3, the
amide unit adopts an s-cissoid conformation and that the
dihedral angle between the planes of the two aromatic rings is
ca. 89Њ (which compares with an angle of 96Њ reported39 for
rhazinilam itself ).
anisotropically refined atoms shown with 50% displacement ellipsoids.
centrations studied (viz. 5, 10, 25, 50 and 100 µM). Compound
3 was also examined for its effects on the polymerisation of
purified tubulin dependent either on glutamate (Fig. 3) or on
microtubule-associated proteins (MAPs) (Fig. 4) and results
similar to those described11 for (Ϫ)-rhazinilam were obtained.
Such data suggest 3 is about 20–30% as active as rhazinilam and
if only one enantiomeric form is active (as is probable) then the
difference between the two compounds [viz. (ϩ)- or (Ϫ)-3 and
(Ϫ)-2] is essentially the same within experimental error. These
results suggest that compound 3 and its derivatives warrant
further evaluation as potential anti-mitotic agents. The
biological evaluation of (Ϫ)-rhazinal (1) has been described
previously.2
(c) Results of biological testing
Experimental
(Ϫ)-Rhazinilam (2) and ( )-B-norrhazinal (3) were evaluated
for their cytotoxic effects on the growth of human CA46
Burkitt lymphoma cells, and IC50 values of 1 and 3 µM, respect-
ively, were observed. The open-ring amino ester precursor, 34,
of 3 gave an IC50 value of 20 µM in the same assay. Both
compounds 2 and 3 arrested cells at G2M phase at all con-
General
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded on a Varian Gemini 300 or Varian
Mercury 300 spectrometer operating at 300 MHz for proton
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the data are given as: chemical shift (δ) (protonicity), where
protonicity is defined as: C = quaternary; CH = methine; CH2 =
methylene; CH3 = methyl; C or CH2 = quaternary or methylene;
CH or CH3 = methine or methyl. The assignments of signals
observed in various NMR spectra were often assisted by
conducting attached proton test (APT), homonuclear (1H/1H)
correlation spectroscopy (COSY), nuclear Overhauser effect
(nOe), and/or heteronuclear (1H/13C) correlation spectroscopy
(HETCOR) experiments.
Infrared spectra (νmax) were recorded on either a Perkin–
Elmer 1800 Fourier Transform Infrared Spectrophotometer or
a Perkin–Elmer Spectrum One instrument as thin films on KBr
plates (for oils) or as KBr discs (for solids).
Analytical thin layer chromatography (TLC) was conducted
on glass-backed 0.2 mm thick silica gel 60 F254 plates (Merck)
and the chromatograms were visualised under a 254 nm UV
lamp and/or by treatment with an alkaline potassium
permanganate dip (3 g KMnO4, 20 g K2CO3, 5 mL 5% aqueous
NaOH, 300 mL water) or a phosphomolybdic acid–ceric
sulfate–sulfuric acid–water dip (37.5 g : 7.5 g : 37.5 mL : 720
mL) followed by heating. The retention factor (Rf) quoted is
rounded to the nearest 0.1. Flash chromatography was con-
ducted according to the method of Still and co-workers41 using
silica gel 60 (mesh size 0.040–0.063 mm) as the stationary phase
and the analytical reagent (AR) grade solvents indicated.
Many starting materials and reagents were available from
the Aldrich Chemical Company or EGA-Chemie and were used
as supplied or simply distilled. Drying agents and other
inorganic salts were purchased from AJAX or BDH Chemicals.
Reactions employing air- and/or moisture-sensitive reagents
and intermediates were carried out under an atmosphere of dry,
oxygen-free nitrogen.
Fig. 3 Effects of compounds 2, 3, Taxol and vinblastine on the
polymerisation of purified tubulin as determined in a reaction sequence
measuring glutamate-dependent assembly, followed by cold-induced
disassembly. Curve 1 = reaction without drug; Curve 2 = reaction with
20 µM 2; Curve 3 = reaction with 60 µM 3; Curve 4 = reaction with 10
µM Taxol; Curve 5 = reaction with 20 µM vinblastine. Reaction
conditions: 0.8 M monosodium glutamate (2 M stock adjusted to pH
6.6 with HCl), 0.4 mM GTP, 10 µM tubulin (1 mg mLϪ1) with DMSO at
4%.
Tetrahydrofuran and diethyl ether were dried using sodium
metal and then distilled, as required, from sodium benzo-
phenone ketyl. Dichloromethane (CH2Cl2) was distilled from
calcium hydride.
Organic solutions obtained from work-up of reaction
mixtures were dried with magnesium sulfate (MgSO4) then
filtered and concentrated under reduced pressure on a rotary
evaporator with the water bath generally not exceeding 40 ЊC.
Melting points were recorded on a Reichert hot-stage appar-
atus and are uncorrected. Elemental analyses were performed
by the Australian National University Microanalytical Services
Unit based in the Research School of Chemistry, The Austral-
ian National University, Canberra, Australia.
Methyl 4-nitrohexanoate (9)
A mixture of methyl acrylate (10 mL, 110 mmol), nitropropane
(14.9 mL, 170 mmol) and NaOH (210 mL of a 0.1 M aqueous
solution, 21 mmol) was stirred vigorously at 18 ЊC for 22 h.
After this time the reaction mixture was saturated with NaCl
(solid), then extracted with diethyl ether (4 × 75 mL). The
combined organic phases were dried, filtered and concentrated
under reduced pressure. Distillation of the resulting pale yellow
residue gave methyl 4-nitrohexanoate (9)23 (12.5 g, 65%) as a
clear, colourless liquid, bp 115–117 ЊC at 1.8 mm Hg (lit.23 92 ЊC
at 1 mm Hg). δH 0.94 (3H, t, J 7.4), 1.82 (1H, m), 1.92–2.38 (5H,
complex m), 3.67 (3H, s), 4.46 (1H, m).
Fig. 4 Effects of compounds 2, 3, Taxol and vinblastine on the
polymerisation of purified tubulin as determined in a reaction sequence
measuring MAPs-dependent assembly, followed by cold-induced
disassembly. Curve 1 = reaction without drug; Curve 2 = reaction with
20 µM 2; Curve 3 = reaction with 120 µM 3; Curve 4 = reaction with 20
µM Taxol; Curve 5 = reaction with 40 µM vinblastine. Reaction
conditions: 0.1 M 4-morpholineethanesulfonate (1 M stock adjusted to
pH 6.9 with NaOH), 0.5 mM GTP, 0.5 mM MgCl2, 20 µM tubulin
(2 mg mLϪ1), heat-treated MAPs at 1.5 mg mLϪ1 with DMSO at 4%.
and 75.4 MHz for carbon nuclei. Chemical shifts were recorded
as δ values in parts per million (ppm). Spectra were acquired
in deuterochloroform (CDCl3) at 20 ЊC unless otherwise stated.
For 1H NMR spectra recorded in CDCl3, the peak due to
Methyl 4-oxohexanoate (10)
A solution of K2CO3 (72.6 g, 0.53 mol) and NaHCO3 (44.2 g,
0.53 mol) in H2O (280 mL) was added to a solution of
nitroalkane 9 (4.60 g, 0.026 mol) in acetone (220 mL) and the
resulting mixture stirred vigorously at 18 ЊC. A solution of
Oxone (17.80 g, 0.029 mol) in H2O (140 mL) was then added
dropwise and the resulting mixture stirred at 18 ЊC for 6 h.
Additional portions of Oxone (17.80 g, 0.029 mol) in H2O
(50 mL) and K2CO3 (18.10 g, 130 mmol) in H2O (50 mL) were
then added and stirring continued. After a further 16 h, more
1
residual CHCl3 (δ 7.26) was used as the internal reference. H
NMR data are recorded as follows: chemical shift (δ) [relative
integral, multiplicity, coupling constant(s) J (Hz), assignment
(where possible)] where multiplicity is defined as: s = singlet;
d = doublet; t = triplet; q = quartet; quin = quintet; m =
multiplet or combinations of the above. The central peak
(δ 77.0) of the CDCl3 triplet was used as the reference for
proton-decoupled 13C NMR spectra. For 13C NMR spectra
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Oxone (8.90 g, 0.014 mol) and K2CO3 (9.00 g, 0.065 mol)
were added, and stirring was continued for another 7 h. The
ensuing material was poured into HCl (100 mL of a conc.
aqueous solution) containing ice (300 g) and the mixture thus
obtained extracted with CH2Cl2 (3 × 250 mL). The combined
organic phases were washed with H2O (1 × 200 mL), and brine
(1 × 200 mL) then dried and filtered. The filtrate was concen-
trated under reduced pressure to give keto-ester 1025 (3.60 g,
95%) as a pale yellow liquid. δH 1.07 (3H, t, J 7.4), 2.48 (2H, q,
J 7.4), 2.61 (2H, m), 2.73 (2H, m), 3.67 (3H, s). This material
was used, without purification, in the next step of the reaction
sequence.
3-(2,2-Dibromo-1-ethylcyclopropyl)propyl toluene-4-sulfonate
(14)
Sodium hydroxide (7.0 mL of a 1 : 1 w/v aqueous solution) was
added to a vigorously stirred solution of alkene 13 (310 mg,
1.16 mmol), bromoform (3.22 g, 12.7 mmol) and benzyltriethyl-
ammonium chloride (50 mg) in benzene (7 mL) maintained at
0 ЊC (ice-bath). The ensuing mixture was stirred vigorously for
16 h (during which time the bath was allowed to warm to
18 ЊC), then H2O (40 mL) was added and the mixture extracted
with diethyl ether (2 × 25 mL). The combined extracts were
dried, filtered and concentrated under reduced pressure to give
a light yellow oil. Subjection of this material to flash chromato-
graphy (silica gel, 9 : 1 v/v hexane–ethyl acetate elution) gave,
after concentration of the appropriate fractions (Rf 0.3), the
title sulfonate 14 (356 mg, 70%) as a clear, colourless oil [Found:
(M ϩ H)ϩ, 438.9569. C15H2079Br2O3S requires (M ϩ H)ϩ,
438.9578); νmax (neat) 2968, 1360, 1188, 1176 cmϪ1; δH 0.96 (3H,
t, J 7.2), 1.33 (2H, m), 1.49–1.89 (6H, complex m), 2.44 (3H, s),
4.05 (2H, m), 7.34 (2H, d, J 8.1), 7.78 (2H, d, J 8.1); δC 10.4,
21.6, 25.7, 27.7, 30.3, 33.1, 33.7, 38.6, 70.2, 127.9, 129.9, 133.0,
144.8; m/z 443 (5%) 441 (8) 439 (5) [(M ϩ H)ϩ], 327 (5), 242
(17), 240 (35), 238 (19), 189 (78), 187 (85), 173 (25), 155 (40),
107 (85), 82 (100), 67 (45).
Methyl 4-methylenehexanoate (11)
NaHMDS (35 mL of a 1 M solution in THF, 35 mmol) was
added to a magnetically stirred suspension of Ph3PMeBr
(9.80 g, 28 mmol) in THF (70 mL) maintained at 18 ЊC under a
nitrogen atmosphere. The resulting yellow mixture was stirred
at 18 ЊC for 1.5 h, then a solution of ketone 10 (3.60 g, 25 mmol)
in THF (15 mL) was added dropwise. Stirring was continued
at 18 ЊC for 15 h and then the reaction mixture diluted with
pentane (100 mL). The resulting precipitate was removed by
filtration, the filtrate concentrated under reduced pressure and
the residue treated with additional pentane (100 mL). Filtration
followed by concentration of the filtrate under reduced pressure
afforded alkene 1126 (1.07 g, 30%) as a pale yellow and volatile
liquid. δH 1.05 (3H, t, J 7.4), 2.05 (2H, m), 2.37 (2H, m), 2.48
(2H, m), 3.68 (3H, s), 4.71 (1H, broad s), 4.76 (1H, broad s).
This material was used, without purification, in the next step
of the reaction sequence.
Methyl 4-(2-nitrophenyl)-1H-pyrrole-2-carboxylate (15)
Copper bronze (512 mg, 8.0 mg-atom) was added to a solution
of methyl 4-iodopyrrole-2-carboxylate29 (252 mg, 1.0 mmol),
2-bromonitrobenzene (882 mg, 3.0 mmol) and Pd(PPh3)3
(30 mg, 0.03 mmol) in DMF (3 mL) and the resulting mixture
subjected to ultrasonication at ca. 18 ЊC for 18 h. After this time
the reaction mixture was diluted with ethyl acetate–hexane
(50 mL of a 1 : 1 v/v mixture) and the separated organic phase
washed with water (3 × 20 mL), ammonia (2 × 10 mL of a 2 M
aqueous solution) and then brine (2 × 10 mL). The separated
organic layer was dried, filtered and concentrated under
reduced pressure to give a light yellow oil. Subjection of this
material to flash chromatography (silica gel, 1 : 1 v/v hexane–
dichloromethane elution) afforded three fractions, A–C.
Concentration of fraction A afforded 2,2Ј-dinitrobiphenyl42
(190 mg, 55%) as a light yellow oil and identical with an
authentic sample.
4-Ethylpent-4-en-1-ol (12)
A solution of ester 11 (3.60 g, 25 mmol) in diethyl ether (25 mL)
was added dropwise to a magnetically stirred suspension of
LiAlH4 (2.10 g, 55 mmol) in diethyl ether (75 mL) maintained
at gentle reflux under a nitrogen atmosphere. The ensuing
mixture was heated at reflux for a further 0.5 h, cooled, stirred
at 18 ЊC for 1 h, then cooled to 0 ЊC (ice-bath) and treated,
dropwise, with KHSO4 (30 mL of a 2 M aqueous solution). The
resulting mixture was heated at reflux for 2 min, then filtered,
while still hot, through a pad of Celite, which was washed with
ether (2 × 10 mL). The combined organic phases were dried,
filtered and concentrated under reduced pressure to give
alcohol 1227 (1.63 g, 57%) as a clear, colourless liquid. δH 1.00
(3H, t, J 7.4), 1.52 (1H, broad s), 1.70 (2H, m), 1.99–2.14 (4H,
complex m), 3.58 (2H, broad t, J 6.7), 4.71 (2H, broad s). This
material was used, without purification, in the next step of the
reaction sequence.
Concentration of fraction B afforded the starting iodo-
pyrrole (132 mg, 52% recovery) as a colourless solid and
identical with an authentic sample.
Concentration of fraction C afforded the title pyrrole 15
(110 mg, 88% at 48% conversion) as a yellow crystalline solid,
mp 105–108 ЊC (lit.7 114 ЊC) (Found: Mϩ
, 246.0645.
ؒ
C12H10N2O4 requires Mϩ , 246.0641); νmax (neat) 3290, 1693,
1525, 1445, 1384, 1282, 1214, 1142, 993, 928, 853, 768, 747
cmϪ1; δH 3.84 (3H, s), 6.97 (1H, t, J 2.1), 7.11 (1H, dd, J 3.0 and
1.8), 7.34 (1H, m), 7.44–7.54 (2H, complex m), 7.65 (1H, dd,
ؒ
4-Ethylpent-4-en-1-yl toluene-4-sulfonate (13)
J 8.1 and 1.2), 10.0 (1H, bs); δC 51.7, 114.6, 120.8, 122.0, 123.2,
A magnetically stirred solution of alcohol 12 (1.09 g, 9.6 mmol)
in CH2Cl2 (100 mL) was cooled to 0 ЊC, then Et3N (1.78 mL,
12.48 mmol), DMAP (100 mg, cat.) and p-toluenesulfonyl
chloride (2.06 g, 10.6 mmol) were added. The resulting solution
was stirred under a nitrogen atmosphere at 4 ЊC for 48 h, then
poured onto a mixture of ice (100 g) and HCl (200 mL of a 1 M
aqueous solution). This mixture was extracted with CH2Cl2
(3 × 100 mL), the combined organic phases washed with
NaHCO3 (1 × 200 mL of a saturated aqueous solution) and
brine (1 × 200 mL), then dried, filtered and concentrated under
reduced pressure to give tosylate 13 (1.95 g, 76%) as a light
yellow oil. δH 0.98 (3H, t, J 7.4), 1.78 (2H, m), 1.93 (2H, q,
J 7.4), 2.04 (2H, m), 2.45 (3H, s), 4.02 (2H, t, J 7.3), 4.60 (1H,
broad s), 4.70 (1H, broad s), 7.34 (2H, d, J 8.2), 7.79 (2H, d,
J 8.2); δC 12.2, 21.6, 26.9 28.6, 31.7, 70.2, 108.6, 127.9, 129.8,
144.7, 149.4 (one signal obscured or overlapping). This slightly
impure material was used, directly, in the next step of the
reaction sequence.
123.5, 127.2, 128.6, 131.1, 131.8, 148.4, 161.6; m/z 246 (Mϩ
,
ؒ
100%), 229 (15), 215 (40), 201 (25), 187 (15), 169 (25), 161 (50),
140 (40), 132 (30), 104 (30).
Methyl 4-(2-nitrophenyl)-1-[3-(2,2-dibromo-1-ethylcyclopropyl]-
1H-pyrrole-2-carboxylate [4 (X ؍ NO2, Y ؍ CO2Me)]
NaHMDS (0.2 mL of a 1 M solution in THF, 0.2 mmol) was
added dropwise to a magnetically stirred solution of pyrrole
15 (50 mg, 0.2 mmol) in THF (4 mL) maintained at 0 ЊC under
a nitrogen atmosphere. After 10 min. a solution of tosylate
14 (110 mg, 0.25 mmol) in THF (1 mL) was added dropwise
and the resulting mixture heated (oil bath) at 65 ЊC while a
gentle stream of nitrogen was employed to remove the solvent.
Heating of the residue was continued for 16 h, and after cooling
the reaction mixture was diluted with H2O (5 mL), then
extracted with CH2Cl2 (2 × 20 mL) to give the title compound 4
(X = NO2, Y = CO2Me) (111 mg, quantitative) as a clear colour-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 6 – 3 0 5
301

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less oil contaminated with traces of the tosylate 14 (Found:
0.70 mmol) in CH2Cl2 (10 mL) was cooled to 0 ЊC, then Et3N
(0.13 mL, 0.91 mmol), DMAP (5 mg, 0.04 mmole) and p-t-
oluenesulfonyl chloride (150 mg, 0.77 mmol) were added. The
resulting solution was stirred under a nitrogen atmosphere at
4 ЊC for 48 h, then poured onto a mixture of ice (10 g) and
HCl (20 mL of a 1 M aqueous solution). This mixture was
extracted with CH2Cl2 (3 × 20 mL) and the combined organic
phases washed with NaHCO3 (1 × 20 mL of a saturated
aqueous solution) and brine (1 × 20 mL), then dried, filtered
and concentrated under reduced pressure to give a 2 : 1 mixture
of diastereomers associated with tosylate 19 (210 mg, 84%) as
a pale yellow oil. δH 0.82 (1H, m), 0.87 (3H, t, J 7.2), 0.99 (1H, t,
J 4.8), 1.17–1.74 (10H, complex m), 2.45 (3H, s), 3.87 (2H, m),
4.09 (2H, m), 7.34 (2H, d, J 8.4), 7.78 (2H, d, J 8.4). This
material was used, without purification, in the next step of the
reaction sequence.
Mϩ , 511.9938. C20H2279Br2N2O4 requires Mϩ , 511.9946); νmax
(neat) 2966, 1709, 1660, 1526, 1441, 1361, 1176, 1106 cmϪ1; δH
0.97 (3H, t, J 7.5), 1.52–2.02 (8H, complex m), 3.82 (3H, s), 4.35
(2H, m), 6.99 (1H, d, J 2.0), 7.01 (1H, d, J 2.0), 7.35 (1H, m),
7.45 (1H, dd, J 7.8 and 1.8), 7.52 (1H, td, J 7.8 and 1.2), 7.66
(1H, dd, J 7.8 and 1.2); δC 10.4, 27.9, 28.1, 31.2, 33.3, 33.8, 39.1,
49.2, 51.2, 117.5, 118.4, 122.4, 123.6, 127.1 (two signals super-
imposed), 128.6, 131.0, 131.8, 149.0, 161.1; m/z 516 (15%) 514
ؒ
ؒ
(30) 512 (15) [Mϩ ], 403 (40) 401 (40), 353 (35), 283 (60), 269
ؒ
(45), 259 (100), 107 (40).
4-Ethylpent-4-enyloxymethylbenzene (16)
NaH (1.20 g, 49 mmol) was added in portions to a magnetically
stirred and ice-cold solution of alcohol 12 (2.80 g, 25 mmol),
benzyl bromide (3.2 mL, 27 mmol) and sodium iodide (200 mg,
1 mmol) in DMF (50 mL) maintained at 18 ЊC under a nitrogen
atmosphere. The resulting mixture was stirred at 18 ЊC for 18 h,
quenched with H2O (25 mL), then partitioned between diethyl
ether (75 mL) and H2O (150 mL). The separated aqueous phase
was extracted with diethyl ether (3 × 75 mL) and the combined
organic phases washed with H2O (3 × 75 mL) and brine (1 × 75
mL), then dried, filtered and concentrated under reduced
pressure to give a light brown liquid. Subjection of this material
to flash chromatography (silica gel, 97 : 3 v/v hexane–diethyl
ether elution) and concentration of the appropriate fractions
2-Ethyl-2-(3-pyrrol-1-ylpropyl)cyclopropanecarboxylic acid
ethyl ester (20)
Pyrrole (31 µL, 0.46 mmol) was added to a magnetically stirred
suspension of KH (18 mg, 0.46 mmol) in DMF maintained
under a nitrogen atmosphere and the resulting solution stirred
at 18 ЊC for 5 min, then a solution of the tosylate 19 (80 mg,
0.23 mmol) in DMF (2 mL) was added. The resulting mixture
was stirred at 18 ЊC for 1.5 h, then quenched with H2O (5 mL)
and partitioned between ethyl acetate (20 mL) and HCl (5 mL
of a 1 M aqueous solution). The separated aqueous phase was
extracted with ethyl acetate (2 × 20 mL) and the combined
organic phases washed with H2O (3 × 40 mL) and brine (1 × 40
mL), then dried, filtered and concentrated under reduced
pressure to give a brown oil. Subjection of this material to flash
chromatography (silica gel, 1 : 1 v/v hexane–diethyl ether
elution) and concentration of the appropriate fractions (Rf 0.6)
gave the title compound 16 (3.50 g, 70%) as a clear, colourless oil
ϩ
(Found: Mϩ , 204.1517. C14H20O requires M . 204.1514); νmax
(neat) 2936, 2854, 1645, 1453, 1104, 889, 734, 696 cmϪ1; δH 1.02
(3H, t, J 7.4), 1.77 (2H, m), 1.97–2.14 (4H, complex m), 3.48
(2H, t, J 6.6), 4.51 (2H, s), 4.71 (2H, br s), 7.25–7.34 (5H,
complex m); δC 12.3 (CH3) 27.9 (CH2), 28.8 (CH2), 32.6 (CH2),
70.1 (CH2), 72.9 (CH2), 107.7 (CH2), 127.5 (CH), 127.6 (CH),
ؒ
ؒ
128.3 (CH), 138.6 (C), 151.0 (C); m/z 204 (Mϩ , 1%), 175 (6),
ؒ
gave a 2 : 1 mixture of diastereomers associated with pyrrole
20 (50 mg, 89%) as a clear, colourless oil (Found: Mϩ
,
ؒ
134 (6), 113 (21), 91 (100).
249.1728. C15H23NO2 requires Mϩ , 249.1729); νmax (neat) 2962,
1722, 1449, 1405, 1281, 1174, 1089, 722 cmϪ1; δH 0.86 (4H, m),
1.05 (1H, m), 1.25 (3H, t, J 6.9), 1.23–1.95 (7H, complex m),
3.80 (2H, m), 4.07 (2H, q, J 6.9), 6.10 (2H, m), 6.61 (2H, m); δC
10.4, 10.8, 14.3, 20.4, 20.6, 21.6, 25.7, 25.9, 26.3, 28.3, 28.9,
ؒ
2-(3-Hydroxypropyl)-2-ethylcyclopropanecarboxylic acid ethyl
ester (18)
A solution of ethyl diazoacetate (0.8 mL, 7.5 mmol) in CH2Cl2
(4 mL) was added, via syringe pump at a rate of 2–3 drops per
minute, to a magnetically stirred solution of alkene 16 (0.5 g,
2.4 mmol) and Rh2(OAc)4 (22 mg, 0.6 mol%) in CH2Cl2 (3 mL)
maintained at 18 ЊC under a nitrogen atmosphere. On com-
pletion of the addition the reaction mixture was filtered
through a silica pad and the filtrate concentrated under reduced
pressure. The residue, containing the diastereoisomeric cyclo-
propanes 17, was dissolved in a mixture of ethyl acetate (20
mL), CH2Cl2 (10 mL) and ethanol (10 mL), then 5% Pd/C (10
mg) was added, and the resulting mixture was stirred under a
balloon of H2 for 22 h. The mixture was then filtered through
a pad of Celite and the filtrate concentrated under reduced
pressure to give a pale orange liquid. Subjection of this material
to column chromatography (silica gel, 1 : 1 v/v diethyl ether–
hexane elution) and concentration of the appropriate fractions
(Rf 0.2) gave a 2 : 1 mixture of the diastereoisomers associated
with alcohol 18 (210 mg, 42%) as a clear, colourless oil [Found:
(M ϩ H)ϩ, 201.1490. C11H20O3 requires (MϩH)ϩ, 201.1491];
νmax (neat) 3424, 2962, 2936, 1723, 1176 cmϪ1; δH 0.81–0.94 (4H,
complex m), 1.05 (1H, q, J 4.7), 1.24 (4H, m), 1.41–1.70 (6H,
complex m), 1.70 (1H, broad s), 3.57 (2/3H, t, J 6.1), 3.62 (4/3H,
t, J 6.3), 4.11 (2H, q, J 7.2); δC 10.8, 11.2, 14.7, 21.0, 21.1, 22.0,
24.9, 26.3, 26.7, 29.8, 30.0, 30.2, 32.0, 32.2, 32.8, 60.6, 60.8,
63.0, 63.1, 173.1, 173.5 (one signal obscured or overlapping);
m/z (DCI) 201 [(M ϩ H)ϩ, 22%] 155 (100), 137 (38), 109 (58),
99 (92).
29.6, 31.3, 31.5, 33.3, 49.4, 49.7, 60.3, 107.9, 108.0, 120.3, 172.4,
172.8 (three peaks obscured or overlapping); m/z 249 (Mϩ
,
ؒ
73%), 220 (43), 204 (50), 176 (39), 162 (46), 148 (71), 134 (60),
94 (65), 81 (100), 80 (88).
Dimethyl 2-(3-hydroxypropyl)-2-ethylcyclopropane-1,1-dicarb-
oxylate (22)
A solution of dimethyl diazomalonate31 (250 mg, 1.5 mmol)
in CH2Cl2 (2 mL) was added, via syringe pump at a rate of
2–3 drops per minute, to a solution of alkene 16 (100 mg,
0.49 mmol) and Rh2(OAc)4 (11 mg, 2 mol %) in CH2Cl2 (2 mL)
maintained at reflux under a nitrogen atmosphere. On com-
pletion of the addition the mixture was heated at reflux for 1 h,
then cooled and filtered through a pad of silica gel and the
filtrate concentrated under reduced pressure to give a light
yellow oil. The residue, containing ether 21, was dissolved
in ethyl acetate–methanol (17 mL of a 10 : 7 v/v mixture), 5%
Pd/C (10 mg) was added and the resulting mixture stirred
magnetically under an atmosphere of H2 at 18 ЊC for 22 h. The
ensuing mixture was filtered through a pad of Celite and the
filtrate concentrated under reduced pressure to give a pale
yellow liquid. Subjection of this material to flash chromato-
graphy (silica gel, 2 : 1 v/v hexane–diethyl ether elution) and
concentration of the appropriate fractions (Rf 0.3) gave the title
cyclopropane 22 (54 mg, 45%) as a clear, colourless liquid
[Found: (M ϩ H)ϩ, 245.1390. C12H20O5 requires (M ϩ H)ϩ,
245.1389); νmax (neat) 3415, 2953, 2878, 1731, 1436, 1289, 1225,
1112, 1061, 897 cmϪ1; δH 0.93 (3H, t, J 7.2), 1.22 (1H, m), 1.41–
1.78 (8H, complex m), 3.56 (2H, t, J 6.3), 3.73 (6H, s); δC 10.5,
2-Ethyl-2-[3-(toluene-4-sulfonyloxy)propyl]cyclopropanecarb-
oxylic acid ethyl ester (19)
A magnetically stirred solution of alcohol 18 (140 mg,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 6 – 3 0 5
302

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24.3, 26.3, 26.4, 29.4, 37.8, 39.7, 52.4, 52.5, 62.4, 169.2, 169.5;
m/z (DCI) 245 [(M ϩ H)ϩ, <1%], 227 (24), 213 (56), 195 (23),
181 (28), 99 (100).
Methyl ( )-1-(2-aminophenyl)-8-ethyl-3-formyl-5,6,7,8-tetra-
hydroindolizin-8-acetate (34)
Na2CO3 (1 mL of a 2 M aqueous solution) was added to a
degassed and magnetically stirred solution of iodopyrrole 33
(52 mg, 0.14 mmol) and Pd(PPh3)4 (6 mg, 4 mole %) in toluene
(2 mL), followed by a solution of 2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine (67 mg, 0.34 mmol) in meth-
anol (0.5 mL). The resulting mixture was heated at 80 ЊC for 2
h, then cooled, diluted with brine (5 mL) and extracted with
ethyl acetate (2 × 10 mL). The combined organic extracts were
dried, filtered and concentrated under reduced pressure to give
a light yellow oil. Subjection of this material to flash chromato-
graphy (silica gel, 2 : 3 v/v ethyl acetate–hexane elution) gave,
2-Ethyl-2-[3-(toluene-4-sulfonyloxy)propyl]cyclopropane-1,1-di-
carboxylic acid dimethyl ester (23)
A
magnetically stirred solution of alcohol 22 (50 mg,
0.21 mmol) in pyridine (3 mL) was cooled to 0 ЊC, then p-tolue-
nesulfonyl chloride (43 mg, 0.23 mmol) was added. The result-
ing solution was stirred under a nitrogen atmosphere at 4 ЊC
for 48 h, then poured onto a mixture of ice (10 g) and HCl
(20 mL of a 1 M aqueous solution). This mixture was
extracted with CH2Cl2 (3 × 20 mL) and the combined organic
phases washed with HCl (1 × 20 mL of a 1 M aqueous solu-
tion), H2O (1 × 20 mL) and brine (1 × 20 mL), then dried,
filtered and concentrated under reduced pressure to give the
tosylate 23 (55 mg, 67%) as a colourless oil. δH 0.87 (3H, t,
J 7.2), 1.20 (1H, m), 1.35–1.71 (7H, complex m), 2.45 (3H, s),
3.70 (3H, s), 3.71 (3H, s), 3.98 (2H, m), 7.34 (2H, J 8.4), 7.78
(2H, d, J 8.4). This material was used, without purification, in
attempts to prepare compound 24 (see Results and discussion
section).
after concentration of the appropriate fractions, the amino-
ester 34 (36 mg, 76%) as a clear, colourless oil (Found: Mϩ
,
ؒ
340.1792. C20H24N2O3 requires Mϩ , 340.1787); νmax 3456, 3369,
1732, 1656, 1617 cmϪ1; δH (C6D6, 2 : 1 mixture of rotamers) 0.60
(3H, m), 1.38–1.85 (6H, complex m), 2.28 (2/3H, d, J 15.5), 2.38
(1/3H, d, J 15.5), 2.72 (2/3H, d, J 15.5), 2.82 (1/3H, d, J 15.5),
3.28 (2H, s, OCH3), 3.30 (2/3H, broad s), 3.31 (1H, s, OCH3),
3.80 (4/3H, broad s), 4.40 (1/3H, m), 4.50 (4/3H, t, J 6.0), 4.64
(1/3H, m), 6.55 (2H, m), 6.85 (1H, m), 7.15–7.40 (2H, complex
ؒ
m), 9.55 (1/3H, s), 9.56 (2/3H, s); m/z 340 (Mϩ , 20%), 237 (30),
ؒ
219 (70), 162 (60), 146 (50), 119 (100), 59 (70).
Methyl ( )-8-ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-
acetate (32)
( )-B-Norrhazinal (3)
Phosphorus oxychloride (70 mg, 0.45 mmol) was added to
a magnetically stirred solution of pyrrole 3135 (92 mg,
0.42 mmol) and DMF (0.4 mL) in ether (5 mL) maintained
at 0 ЊC. After 0.5 h the ice-bath was removed and the
mixture stirred at 18 ЊC for 3 h before addition of ether (20 mL)
and Na2CO3 (20 mL of a 2 M aqueous solution). Stirring
was continued for a further 10 min then the organic phase
was separated and the aqueous phase extracted with diethyl
ether (1 × 25 mL). The combined organic extracts were
dried, filtered and concentrated under reduced pressure to give
a light yellow oil. Subjection of this material to flash chromato-
graphy (silica gel, 1 : 4 v/v ethyl acetate–hexane elution)
gave, after concentration of the appropriate fractions, the
2-formylpyrrole 32 (100 mg, 95%) as a white crystalline
Method A. Potassium hydroxide (2.25, 40 mmol) was added
to a magnetically stirred solution of the amino-ester 34 (15 mg,
0.044 mmol) in ethanol (5 mL) maintained at 18 ЊC under a
nitrogen atmosphere. After 48 h the reaction mixture was acid-
ified to pH 5 (with 2 M aqueous HCl), then extracted with ethyl
acetate (2 × 5 mL). The combined organic extracts were dried,
filtered and concentrated under reduced pressure to give a light
yellow oil. This material was dissolved in THF (10 mL) and
treated with the salt derived from 2-chloro-4,6-dimethoxy-
triazine (210 mg, 1.2 mmol) and N-methylmorpholine (40 mg,
0.4 mmol). The resulting solution was stirred for 2 h at 18 ЊC,
then diluted with ethyl acetate (10 mL) and brine (5 mL). The
separated aqueous phase was extracted with ethyl acetate (1 ×
10 mL) and the combined organic extracts dried, filtered and
concentrated under reduced pressure to give a light yellow oil.
Subjection of this material to thin layer chromatography (silica
gel, 7 : 3 v/v ethyl acetate–hexane elution) and extraction of the
appropriate band gave ( )-B-norrhazinal (3) (7 mg, 74%) as a
cream-coloured and crystalline solid, no mp but decomposition
solid, mp 69–70 ЊC (Found: Mϩ , 249.1361. C14H19NO3
ؒ
requires Mϩ , 249.1365); νmax 2967, 1731, 1659, 1181, 785 cmϪ1
;
ؒ
δH 0.83 (3H, t, J 7.5), 1.78 (2H, q, J 7.5), 1.81 (1H, m), 1.96
(3H, m), 2.61 (2H, m), 3.58 (3H, s), 4.35 (2H, t, J 6), 6.02
(1H, d, J 4.2), 6.86 (1H, d, J 4.2), 9.41 (1H, s); δC 8.7, 19.5, 28.8,
33.3, 37.9, 44.3, 45.3, 51.4, 107.2, 124.4, 130.7, 145.5, 171.3,
178.7; m/z 249 (Mϩ , 45%), 220 (45), 176 (100) 160 (45), 132
ؒ
above 150 ЊC (crystals suitable for X-ray analysis were obtained
from ether–hexane) (Found: Mϩ
, 308.1523. C19H20N2O2
ؒ
(60).
requires Mϩ , 308.1525); νmax 3287, 1722, 1659 cmϪ1; δH 0.68
(3H, t, J 7.5), 1.44–1.68 (3H, complex m), 1.87 (1H, dt, J 13.5
and 3.5), 1.94–2.03 (1H, complex m), 2.15 (1H, d, J 11.5), 2.40
(1H, td, J 13.5 and 3.6), 2.79 (1H, d, J 12.4), 4.08 (1H, m), 4.83
(1H, dd, J 14.3 and 6.0), 6.71 (1H, s), 7.13 (1H, m), 7.17 (1H,
broad s), 7.28–7.42 (3H, complex m), 9.46 (1H, s); δC 8.1, 18.4,
ؒ
Methyl ( )-8-ethyl-3-formyl-5,6,7,8-tetrahydro-1-iodoindolizin-
8-acetate (33)
Iodine (92 mg, 0.36 mmol) was added to a magnetically stirred
mixture of the pyrrole 32 (81 mg, 0.33 mmol) and silver
trifluoroacetate (89 mg, 0.36 mmol) in chloroform (5 mL)
maintained at 0 ЊC (ice-bath) under a nitrogen atmosphere. The
reaction mixture was then warmed to 18 ЊC, stirred at this
temperature for 4 h (whilst being protected from light), then
treated with Na2S2O5 (1 mL of a 20% w/v aqueous solution)
and brine (5 mL). The resulting mixture was extracted with
CH2Cl2 (2 × 20 mL), and the combined organic extracts were
dried, filtered and concentrated under reduced pressure to give
28.3, 33.9, 38.3, 41.2, 45.3, 120.2, 125.2, 125.7, 127.6, 128.2,
131.1, 131.4, 134.8, 135.8, 143.2, 173.7, 179.0; m/z 308 (Mϩ
,
ؒ
56%), 279 (75), 251 (42), 237 (100).
Method B. Potassium tert-butoxide (40 mg, 0.37 mmol) was
added to a solution of the amino-ester 34 (42 mg, 0.12 mmol) in
tert-butanol (5 mL) and the resulting mixture stirred under a
nitrogen atmosphere at 18 ЊC for 3 h. Water (5 mL) and NH4Cl
(5 mL of a saturated aqueous solution) were added to the
resulting mixture, which was extracted with CH2Cl2 (3 × 10
mL). The combined organic extracts were dried, filtered and
concentrated under reduced pressure to give a light yellow oil.
Subjection of this material to flash chromatography (silica gel,
gradient elution with ether, then ethyl acetate elution) afforded
two fractions A and B.
the iodopyrrole 33 (105 mg, 75%) as a clear, colourless oil
ϩ
(Found: Mϩ , 375.0331. C14H18INO3 requires M , 375.0331);
νmax 2961, 1732, 1661 cmϪ1; δH 0.78 (3H, t, J 7.5), 1.74–2.18 (5H,
complex m), 2.34 (1H, m), 2.70 (1H, d, J 15.4), 3.23 (1H, d,
J 15.4), 3.60 (3H, s), 4.41 (2H, t, J 6), 7.03 (1H, s), 9.38 (1H, s);
δC 8.7, 19.9, 29.0, 30.7, 38.7, 42.2, 46.2, 51.6, 58.6, 132.1, 133.1,
ؒ
ؒ
142.3, 171.4, 178.1; m/z 375 (Mϩ , 55%), 302 (75), 219 (100), 160
ؒ
(25).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 6 – 3 0 5
303

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132.2, 133.3, 143.0, 173.8, 178.0; m/z 389 (Mϩ , 60 %), 360 (15),
ؒ
Concentration of fraction A afforded the amino-ester 34
(7 mg, 17% recovery), identical, in all respects, with an
authentic sample.
330 (10), 302 (100), 233 (95), 175 (15), 160 (15), 146 (15).
Concentration of fraction B afforded ( )-B-norrhazinal (3)
(22 mg, 78% at 83% conversion), identical, in all respects, with
the material obtained by Method A.
Methyl ( )-1-(2-aminophenyl)-8-ethyl-3-formyl-5,6,7,8-tetra-
hydroindolizin-8-propionate (41)
Na2CO3 (1 mL of a 2 M aqueous solution), then a solution of
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzeneamine
(20 mg, 0.093 mmol) in methanol (0.5 mL) were added to a
degassed and magnetically stirred solution of iodopyrrole 40
(35 mg, 0.090 mmol) and Pd(PPh3)4 (5 mg) in toluene (2 mL)
maintained under a nitrogen atmosphere. The resulting mixture
was heated at 90 ЊC for 0.5 h, at which time further portions of
the boronate ester (10 mg) and Pd(PPh3)4 (5 mg) were added.
After a further 1 h of heating the reaction mixture was cooled,
diluted with brine (5 mL) and extracted with diethyl ether
(3 × 10 mL). The combined organic extracts were dried, filtered
and concentrated under reduced pressure to give a light yellow
oil. Subjection of this material to flash chromatography (silica
gel, diethyl ether elution) gave, after concentration of the
appropriate fractions, the amino-ester 41 (20 mg, 64% yield) as
Methyl ( )-8-ethyl-5,6,7,8-tetrahydroindolizin-8-propionate (38)
DCC (206 mg, 1 mmol) was added to a magnetically stirred
solution of the acid (100 mg, 0.45 mmol) derived from
hydrolysis of nitrile 3740 and DMAP (5 mg, 0.04 mmol) in
dichloromethane–methanol (4 mL of a 3 : 1 v/v mixture) main-
tained at 18 ЊC under a nitrogen atmosphere. After 3 h water
(10 mL) was added to the reaction mixture, which was then
extracted with dichloromethane (3 × 20 mL). The combined
organic extracts were dried, filtered and concentrated under
reduced pressure to give a light yellow oil. Subjection of
this material to flash chromatography (silica gel, 1 : 9 v/v ethyl
acetate–hexane elution) gave, after concentration of the
appropriate fractions, ester 38 (75 mg, 72%) as a clear, colour-
less oil (Found: Mϩ , 235.1576. C14H21NO2 requires Mϩ
235.1572); νmax 3097, 2948, 2876, 1738, 1195, 1170, 706 cmϪ1
,
;
a clear, colourless oil (Found: Mϩ , 354.1947. C21H26N2O3
ؒ
ؒ
ؒ
requires Mϩ , 354.1943); νmax 3465, 3368, 2951, 1732, 1657
ؒ
δH 0.84 (3H, t, J 7.5), 1.54–1.71 (4H, complex m), 1.86–2.00
(4H, complex m), 2.28 (2H, m), 3.63 (3H, s), 3.88 (2H, t, J 6.5),
5.85 (1H, d, J 3.5), 6.10 (1H, d, J 3.5), 6.45 (1H, bs); δC 8.5, 20.0,
29.7, 30.8, 33.1, 34.4, 37.3, 45.3, 51.5, 104.1, 107.1, 118.6, 134.6,
cmϪ1; δH (ca. 1 : 1 mixture of rotamers) 0.77 (3/2H, t, J 7.8), 0.80
(3/2H, t, J 7.8), 1.40–2.38 (12H, complex m), 3.59 (3/2H, s),
3.66 (3/2H, s), 4.24–4.60 (2H, complex m), 6.72 (2H, m), 6.80
(1H, d, J 3.3), 7.04 (1H, m), 7.14 (1H, dt, J 7.8 and 1.5), 9.42(8)
174.6; m/z 235 (Mϩ , 55%), 206 (80), 174 (50), 148 (100), 146
(1/2H, s), 9.42(9) (1/2H, s); m/z 354 (Mϩ , 100%), 325 (50), 293
ؒ
ؒ
(48), 133 (35), 118 (30).
(15), 267 (65), 239 (45), 237 (30), 209 (25), 176 (20), 130 (10).
Methyl ( )-8-ethyl-3-formyl-5,6,7,8-tetrahydroindolizin-8-
propionate (39)
( )-Rhazinal [( )-1]
Potassium hydroxide (2.0 g, 35.6 mmol) was added to a
magnetically stirred solution of the amino-ester 41 (13 mg,
0.036 mmol) in ethanol (3 mL) maintained at 18 ЊC under a
nitrogen atmosphere. After 3 h the reaction mixture was
acidified to pH 5 (with 2 M aqueous HCl) and extracted with
dichloromethane (3 × 4 mL). The combined organic extracts
were dried, filtered and concentrated under reduced pressure to
give a light yellow oil. A solution of this material in dichloro-
methane (5 mL) was treated with EDCI (10 mg, 0.05 mmol)
and DMAP (5 mg, 0.04 mmol), then stirred at 18 ЊC under a
nitrogen atmosphere for 3 h. At this point water (2 mL) and
HCl (2 drops of a 2 M aqueous solution) were added, and the
separated aqueous phase was extracted with dichloromethane
(2 × 3 mL). The combined organic extracts were then dried,
filtered and concentrated under reduced pressure to give a light
yellow oil. Subjection of this material to flash chromatography
(silica gel, ethyl acetate elution) gave, after concentration of the
appropriate fractions, ( )-rhazinal [( )-1]1 (8 mg, 68% yield) as
a white crystalline solid, mp 234–236 ЊC (crystals suitable for
Phosphorus oxychloride (35 mg, 0.23 mmol) was added to
a magnetically stirred solution of the pyrrole 38 (50 mg,
0.212 mmol) and DMF (0.2 mL, 2.58 mmol) in ether (5 mL)
maintained at 0 ЊC (ice-bath) under a nitrogen atmosphere.
After 0.5 h the ice-bath was removed and the reaction mixture
stirred at 18 ЊC for 3 h, then treated with Na2CO3 (5 mL of a
2 M aqueous solution). Stirring was continued for 10 min,
then diethyl ether (10 mL) was added and the organic phase
separated. The aqueous phase was extracted with ether (1 ×
10 mL) and the combined organic phases dried, filtered and
concentrated under reduced pressure to give pyrrole 39 (44
mg, 78%) as a clear, colourless oil (Found: Mϩ , 263.1525.
ؒ
C15H21NO3 requires Mϩ , 263.1521); νmax (neat) 2926, 1738,
ؒ
1659 cmϪ1; δH 0.82 (3H, t, J 7.5), 1.67 (4H, m), 1.96 (4H, m),
2.20 (2H, m), 3.61 (3H, s), 3.43 (2H, m), 6.00 (1H, d, J 4), 6.87
(1H, d, J 4), 9.39 (1H, s); δC 8.5, 19.5, 28.8, 29.5, 33.2, 34.7, 38.0,
45.4, 51.7, 107.5, 124.5, 130.8, 146.0, 174.0, 178.5; m/z 263
(Mϩ , 50%), 234 (65), 176 (100), 174 (55), 146 (30).
ؒ
X-ray analysis were obtained from CH2Cl2–hexane) (Found:
ϩ
Mϩ , 322.1683. C20H22N2O2 requires M , 322.1681); νmax 3180,
2919, 1660 cmϪ1; δH 0.71 (3H, t, J 7.2), 1.24 (2H, m), 1.53 (2H,
m), 1.76 (1H, td, J 13.5 and 3.3), 1.90–2.06 (2H, complex m),
2.19 (1H, m), 2.42 (1H, t, J 12.5), 2.46 (1H, t, J 10.5), 3.98 (1H,
ddd, J 14.0, 12.0 and 1.8), 4.78 (1H, dd, J 14.0 and 5.5), 6.54
(1H, s), 6.80 (1H, bs), 7.24 (1H, d, J 7.8), 7.30–7.44 (3H, com-
plex m), 9.39 (1H, s); δC 8.2, 18.5, 28.0, 29.8, 31.9, 36.5, 39.6,
46.3, 120.5, 125.6, 127.3, 127.7, 129.0, 130.1, 131.3, 137.5,
ؒ
ؒ
Methyl ( )-8-ethyl-3-formyl-5,6,7,8-tetrahydro-1-iodoindolizin-
8-propionate (40)
Iodine (46 mg, 0.18 mmol) was added to a magnetically stirred
mixture of pyrrole 39 (44 mg, 0.167 mmol) and silver tri-
fluoroacetate (40 mg, 0.18 mmol) in chloroform (5 mL)
maintained at 0 ЊC (ice-bath) under a nitrogen atmosphere.
After addition was complete the ice-bath was removed and the
reaction mixture stirred at 18 ЊC for 4 h with protection from
light. Na2S2O5 (1 mL of a 20% aqueous solution) and brine
(5 mL) were added to the reaction mixture, which was then
extracted with CH2Cl2 (3 × 10 mL). The combined extracts
were dried, filtered and concentrated under reduced pressure to
give the iodopyrrole 40 (71 mg, quantitative) as a clear, colour-
138.2, 141.3, 176.7, 178.8; m/z 322 (Mϩ , 30%), 293 (100), 265
ؒ
(30), 237 (35).
X-Ray crystallographic analysis of compound ( )-1
C20H22N2O2, Mr = 322.41, T = 200.0(1) K, monoclinic, space
group P21/n, Z = 4, a = 11.1081(3), b = 12.6796(4), c =
11.6659(4)Å, β = 101.2591(13)Њ, U = 1611.5 (1) Å3, ρcalc = 1.329 g
cmϪ3, F(000) = 688, µ(MoKα) = 0.086 mmϪ1, numerical absorp-
tion correction applied, 1493 unique data (2Θmax = 40.0Њ), with
902 I >3σI ); R = 0.097, Rw = 0.085, S = 0.835. The only crystals
less oil (Found: Mϩ , 389.0489. C15H20INO3 requires Mϩ
,
ؒ
ؒ
389.0488); νmax (neat) 2950, 1736, 1661 cmϪ1; δH 0.80 (3H, t,
J 7.5), 1.58–1.98 (6H, complex m), 2.15 (3H, m), 2.60 (1H, m),
3.65 (3H, s), 4.30 (1H, m), 4.42 (1H, m), 7.03 (1H, s), 9.37 (1H,
s); δC 8.6, 19.9, 28.4, 29.6, 31.1, 32.9, 39.5, 46.4, 51.7, 59.0,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 6 – 3 0 5
304

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17 O. Baudoin, M. Cesarlo, D. Guénard and F. Guéritte, J. Org. Chem.,
ever obtained, even after exhaustive attempts at crystal growth,
were very fine needles. The largest available had dimensions
of 35 × 45 × 135 µm and was used in this experiment. No
diffraction was observable above Θ = 20Њ.
Images were measured on a Nonius Kappa CCD diffract-
ometer43 (graphite monochromator, λ = 0.71073 Å) and data
extracted using the DENZO package.44 Structure solution was
by direct methods (SIR92)45 and refinement was by full matrix
least-squares on F using the CRYSTALS46 program package.
CCDC 195978. See http://www.rsc.org/suppdata/ob/b2/
b209992f/ for crystallographic data in CIF or other electronic
format.
2002, 67, 1199.
18 See, for example: (a) M. G. Banwell, B. L. Flynn, E. Hamel and
D. C. R. Hockless, Chem. Commun., 1997, 207; (b) M. G. Banwell,
B. L. Flynn and D. C. R. Hockless, Chem. Commun., 1997, 2259;
(c) M. G. Banwell, A. M. Bray, A. J. Edwards and D. J. Wong, New J.
Chem., 2001, 25, 1347; (d ) M. G. Banwell, A. M. Bray, A. J. Edwards
and D. J. Wong, J. Chem. Soc., Perkin Trans. 1, 2002, 1340.
19 M. Banwell, A. Edwards, J. Smith, E. Hamel and P. Verdier-Pinard,
J. Chem. Soc., Perkin Trans. 1, 2000, 1497.
20 In contrast, intermolecular variants are well known – see for
example: R. Lueoend and R. Neier, Helv. Chim. Acta, 1991, 74, 91
and references cited there-in.
21 For a recent and comprehensive review of pyrrole chemistry which
covers this aspect see : D. St. C. Black, Pyrroles and their benzo
derivatives: reactivity, in Comprehensive Heterocyclic Chemistry II,
ed. C. W. Bird, Elsevier, Oxford, UK, 1996, vol. 2, pp. 39–117.
22 For related work involving hetero-atom centered nucleophilic
capture of π-allylcations generated by electrocyclic ring-opening of
gem-dibromocyclopropanes see: M. G. Banwell, J. E. Harvey
and K. A. Jolliffe, J. Chem. Soc., Perkin Trans. 1, 2001, 2002 and
references cited there-in.
23 R. Ballini and G. Bosica, Eur. J. Org. Chem., 1998, 355.
24 P. Ceccherelli, M. Curini, M. C. Marcotullio, F. Epifano and
O. Rosati, Synth. Commun., 1998, 28, 3057.
25 K. Mori, H. Takikawa, Y. Nishimura and H. Horikiri, Liebigs Ann.,
1997, 327.
26 M. E. Kuehne, C. L. Kirkemo, T. H. Matsko and J. C. Bohnert,
J. Org. Chem., 1980, 45, 3259.
27 J. Hartmann and M. Schlosser, Helv. Chim. Acta, 1976, 59, 453.
28 N. Shimizu, T. Kitamura, K. Watanabe, T. Yamaguchi, H. Shigyo
and T. Ohta, Tetrahedron Lett., 1993, 34, 3421.
29 P. Bélanger, Tetrahedron Lett., 1979, 2505.
30 S. Danishefsky, Acc. Chem. Res., 1979, 12, 66.
Acknowledgements
We thank the Institute of Advanced Studies for financial
support, including the provision of post-Doctoral Fellowships
(to KAJ and JAS) and AMRAD (Melbourne) for a post-Doc-
toral Research Award (to JAS). Dr S. Marcuccio (CSIRO
Molecular Science, Clayton) and Dr H. Schuhbauer (SKW,
Trostberg) are thanked for supplying generous quantities
of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine
and
2-chloro-4,6-dimethoxy-1,3,5-triazene,
respectively.
Dr Françoise Guéritte (CNRS, Gif-sur-Yvette) is thanked for
providing an authentic sample of (Ϫ)-rhazinilam. The
assistance of Dr Carl Braybrook (CSIRO Molecular Science,
Melbourne) in obtaining mass spectral data is gratefully
acknowledged.
31 M. P. Doyle, M. A. McKervey and T. Yeo, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides, Wiley, New York, 1998.
32 M. G. Banwell, A. M. Bray, A. C. Willis and D. J. Wong, New J.
Chem., 1999, 23, 687.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 6 – 3 0 5
305