Exploiting multiple nucleophilic sites on pyrrole for the assembly of polyheterocyclic frameworks: Application to a formal total synthesis of (±)-aspidospermidine

Article abstract of DOI:10.1039/b208821e

The tricyclic ketone 19, an advanced intermediate in Aube's recently reported synthesis of aspidospermidine (4), is prepared in twelve steps from pyrrole (3). The key transformations involve a previously described intramolecular Michael addition reaction of pyrrole 10 and intramolecular Friedel-Crafts type cyclisation of the derived carboxylic acid 15 to ketone 16. Careful hydrogenation of this last compound afforded the fully saturated alcohol 17 which was readily oxidised to the target ketone 19.

Full text of DOI:10.1039/b208821e

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Exploiting multiple nucleophilic sites on pyrrole for the assembly
of polyheterocyclic frameworks: application to a formal total
synthesis of ( )-aspidospermidine
1
Martin G. Banwell and Jason A. Smith
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 0200, Australia.
E-mail: mgb@rsc.anu.edu.au
Received (in Cambridge, UK) 13th September 2002, Accepted 18th October 2002
First published as an Advance Article on the web 12th November 2002
The tricyclic ketone 19, an advanced intermediate in Aubé’s recently reported synthesis of aspidospermidine (4), is
prepared in twelve steps from pyrrole (3). The key transformations involve a previously described intramolecular
Michael addition reaction of pyrrole 10 and intramolecular Friedel–Crafts type cyclisation of the derived carboxylic
acid 15 to ketone 16. Careful hydrogenation of this last compound afforded the fully saturated alcohol 17 which was
readily oxidised to the target ketone 19.
Introduction
In connection with a general program directed towards the syn-
thesis of pyrrole-containing natural products now underway in
these laboratories1 we have begun to more fully appreciate
the manifold nucleophilic properties of this readily available
five-membered aromatic heterocycle.2 Such properties have
been exploited in our recently described syntheses of the
marine alkaloid longamide B3 and ( )-B-norrhazinal (1),4 a
biologically active analogue of the terrestrial natural product
(Ϫ)-rhazinilam (2) which possesses intriguing anti-mitotic
properties.5 Our synthesis of compound 1 exploited the nucleo-
philic character of both N-1 and C-2 of pyrrole (3), with the
former centre participating in an intermolecular alkylation
reaction and the latter in a facile intramolecular Michael
addition to a tethered acrylate. Herein we report extension
of such chemistries to a formal total synthesis of the alkaloid
( )-aspidospermidine [( )-4] wherein the nucleophilic character
of N-1, C-2 and C-3 of pyrrole are all engaged in the course
the conditions defined by Synder9 to give, after acidic work-up,
of assembling an advanced precursor to this target molecule.
Thus, our synthesis starts from abundant pyrrole, employs
simple reagents throughout and, in keeping with the majority
of previous routes, proceeds via a hydrolilolidone precursor
(incorporating the CDE-ring substructure of target 4) which
can be subjected to a “one-pot” Fischer indolization reaction to
complete the synthesis. Whilst aspidospermidine (4) is biologic-
ally inactive it embodies the pentacyclic framework associated
with a number of pharmacologically significant Aspidosperma
alkaloids including vindoline and the related “dimers” vinblast-
ine and vincristine.6 As such, compound 4 has been a popular
synthetic target for “showcasing” new methodologies. It was
first prepared by Stork and Dolfini in 19637 and since this time
numerous additional and ingenious approaches have been
described8 including several more recent ones employing novel
radical or ionic cyclisation sequences and another exploiting an
intramolecular Schimdt reaction.
the N-1 alkylation product 7 (90%). This last compound was
then converted, in one-pot, into the corresponding Weinreb
amide 8 (87%) by using our recently described10 adaptation of
the Mukaiyama amide synthesis. Reaction of amide 8 with
ethyl magnesium bromide then afforded, after work-up at
Ϫ40 ЊC (in order to avoid formation of unwanted products of
cyclisation between the carbonyl carbon and C-2 of the
pyrrole), the ethyl ketone 9 (100%). Wadsworth–Emmons
olefination of the latter compound using the anion derived
from methyl diethylphosphonoacetate then afforded the β,β-
disubstituted acrylate 10 (77%). The use of methyl diethyl-
phosphonoacetate is preferred for this olefination as the sodium
salt is soluble in THF, unlike the salts of the triethyl and tri-
methyl phosphonoacetates. The acrylate 10 was obtained as a
1:1 mixture of geometric isomers which were separated
chromatographically for the purposes of independent charac-
terization. In keeping with the behaviour of other acrylates
incorporating tethered nucleophiles,11 compound 10 engaged in
a Lewis-acid (in this case AlCl3) mediated intramolecular
Michael addition reaction wherein C-2 of the tethered pyrrole
acts as the nucleophilic centre and in this way the indolizidine
11 was obtained in 83% yield. Whilst the intermolecular reac-
tion of acrylates and related species with pyrroles is well
Results and discussion
The reaction sequence leading from the readily prepared potas-
sium salt, 5, of pyrrole to target 4 is shown in Scheme 1. Thus,
following on from our work4 on the synthesis of ( )-B-
norrhazinal, salt 5 was reacted with γ-butyrolactone (6) under
DOI: 10.1039/b208821e
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This journal is © The Royal Society of Chemistry 2002
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Scheme 1 Reagents and conditions: (i) 160 ЊC, 2 h; (ii) H3CNHOCH3ؒHCl (1.2 mole equiv.), Et3N (1.2 mole equiv.), pyridine N-oxide disulfide (1.5
mole equiv.), Bu3P (1.5 mole equiv.), CH2Cl2, 18 ЊC, 16 h; (iii) (a) EtMgBr (1.7 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.), THF, 18 ЊC, 48 h; (v) AlCl3
(5 mole equiv.), Et2O, 18 ЊC, 5 h; (vi) DIBAL-H (2 mole equiv.), CH2Cl2, Ϫ78 ЊC, 0.16 h; (vii) MeSO2Cl (1 mole equiv.), Et3N (1 mole equiv.), CH2Cl2,
0–18 ЊC, 1.0 h; (viii) NaCN (5 mole equiv.), DMPU, 18 ЊC, 48 h; (ix) KOH (26 mole equiv.), H2O–MeOH, reflux, 16 h then aq. HCl; (x) HCl (excess of
a 5 M aqueous solution), 18 ЊC, 1 h; (xi) H2 (1 atm.), PtO2 (cat.), AcOH, 18 ЊC, 18 h; (xii) Dess–Martin periodinane (3 mole equiv.), CH2Cl2, 0–18 ЊC,
1.0 h; (xiii) see reference 8o; (xiv) H2 (1 atm.), 5% Rh on Al2O3 (cat.), AcOH–EtOH, 18 ЊC, 18 h; (xv) LiAlH4 (excess), THF, 66 ЊC, 1.5 h.
known,12 to the best of our knowledge the conversion 10
11
of the several possible stereoisomeric tetrahydro-derivatives
since each of these should, in principle, engage in a Fisher-
indolization reaction with phenylhydrazine so as to give, after
“reductive work-up”, ( )-aspidospermidine.7,8o In the event,
reaction of an acetic acid solution of compound 16 with
dihydrogen in the presence of PtO2 at 18 ЊC for 18 h afforded a
ca. 1:1 mixture of what are tentatively assigned as alcohol 17
and the deoxygenated congener 18. The stereochemistries
assigned to these reduction products can be rationalized (Fig. 1)
on the basis that initial hydrogenation of substrate 16 occurs at
the pyrrole double bond remote from the carbonyl group to
give compound 21. This suggestion is supported by the observ-
ation (vide infra) that hydrogenation of pyrrole 16 under milder
conditions (5% Rh on Al2O3) does indeed give the dihydro-
derivative 21. Reduction of the latter compound then occurs at
the carbonyl group and on the opposite face to the steric-
ally demanding and angular ethyl group to afford the allylic
alcohol 23. Compound 23, in turn, engages in a hydroxy-group
directed hydrogenation of the remaining double bond to deliver
the observed saturated alcohol 17 incorporating an all-cis
arrangement of the angular substituents. An alternate mode
of reaction of intermediate 23 could involve hydrogenolytic
removal of the OH group (a process which may well be
facilitated by the ring nitrogen) then reduction of the resulting
represents the first example of the equivalent intramolecular
process. As a necessary prelude to construction of the six-
membered C-ring of target 4, which was to be carried out via
intramolecular acylation at C-3 of the pyrrole backbone, one-
carbon homologation of ester 11 was required. To this end
rather traditional methods were employed involving initial
DIBAL-H-mediated reduction to the 1Њ-alcohol 12 (75%)
which was immediately subject to mesylation under the Cross-
land–Servis conditions.13 The resulting mesylate 13 (95%) was
then subject to reaction with a five-fold excess of sodium cyan-
ide in N,NЈ-dimethylpropyleneurea (DMPU)14 and in this
manner the target nitrile 14 (91%) was readily obtained. In
principle, compound 14 could participate in the foreshadowed
intramolecular acylation reaction to give the target tricyclic
ketone 16. In practice, however, such a conversion could not be
achieved so the nitrile was hydrolysed to the corresponding
acid 15 (88%) under standard conditions. The latter compound
readily engaged in the required Friedel–Crafts reaction upon
exposure to 5 M aqueous HCl so as to form ketone 16 (72%)
which incorporates the CDE-ring substructure associated with
the monomeric aspidospermidine alkaloids including 4.
With the bis-annulated pyrrole 16 in hand the completion of
the synthesis of compound 4 required its reduction to any one
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Fig. 2 Intermediates associated with the LiAlH4-promoted reduction
of compound 21 to product 22.
Fig. 1 Intermediates associated with the 5% PtO2-catalysed reduction
of compound 16 to products 17 and 18.
our own. Nevertheless, our data (see Experimental) are fully
consistent with the assigned structure. In particular, the infra-
red spectrum shows a carbonyl stretching band at 1717 cmϪ1
which is indicative16,17 of hydrolilolidones embodying the illus-
trated ABC ring junction stereochemistries (cf. an absorption at
1708 cmϪ1 for ketone 19). Unfortunately, all attempts (including
those involving application of the conditions defined by Aubé
enamine (24) wherein hydrogen is delivered to the α-face
(i.e. opposite the angular ethyl group) thereby affording the
deoxygenated product 18. The structure of compound 17 fol-
lows from the observation that subjection of the mixture of this
compound and co-product 18 to reaction with the Dess–Martin
periodinane15 gave the known ketone 198o (28% from 16) which
could, at this stage, be readily separated from the saturated
amine (18) by flash chromatography. After allowance is made
for changes in chemical shift induced by varying pH (due to
for the conversion 19
4) to engage this material in the
Fischer indolisation reaction so as to produce aspidosperimid-
ine (4) have failed thus far. This disappointing result is not
entirely surprising as it has been noted8o that application of the
Fischer indolisation process to the synthesis of Aspidosperma
alkaloids from precursors such as 19 and 22 can be capricious
especially when carried out on a small scale.
differing amounts of DCl present in the solvent) the 1H and 13
C
NMR spectral data derived from amino ketone 19 were judged
to be in good agreement with those reported by Aubé8o for the
corresponding enantiomerically pure material. In particular,
the profiles of the complex proton envelopes observed in the
1H NMR spectra of the two samples represent a very good
match indeed. In contrast, the equivalent spectrum of isomer
22 (see below) looks distinctly different. The acquisition of
ketone 19 constitutes a formal total synthesis of ( )-aspido-
spermidine (4) since Aubé8o has converted, in a one-pot
process, the former compound into the latter (accompanied by
small amounts of isomer 20) using Stork’s original Fischer
indolization strategy.
In an effort to provide a higher yielding route to a CDE-ring
precursor of aspidospermidine, alternate methods for the
reduction of pyrrole 16 were examined but with limited success.
Thus, exposure of an ethanol–acetic acid solution of com-
pound 16 to dihydrogen in the presence of rhodium on alumina
afforded the ketoenamine 21 (80% at 50% conversion) which
could be reduced to the fully saturated ketone 22 (65%) on
treatment with lithium aluminium hydride. The illustrated
stereochemistry for amino ketone 22 follows from mechanistic
considerations and by analogy with the production of the
same and a closely related compound as described by Ban16 and
Saxton,17 respectively. Thus, the reduction of compound 21 is
probably best interpreted (Fig. 2) as involving initial α-face
selective hydride delivery to the iminium type-carbon C-9b
highlighted in the zwitterionic resonance contributing form
(21a) of the substrate. The ensuing enolate 25 would then be
quenched, upon aqueous work up, to give ketone 22 and/or
isomer 26. Our molecular mechanics calculations as well as
work by both Ban and Saxton suggests that compounds such
as 26 which incorporate a cis A/C ring junction and ketone
carbonyl at C-9 are more strained (by several kcal molϪ1) than
the epimer (e.g. 22) possessing the equivalent trans ring junction
and that under conditions of thermodynamic control produc-
tion of the latter system will be favoured. Unfortunately, whilst
compound 22 has been described previously16 there are no
spectral data available in the literature for comparison with
Conclusions
The work described here demonstrates the potential for exploit-
ation, in both inter- and intra-molecular reactions, of the three
distinct nucleophilic centres (viz. N-1, C-2 and C-3) associated
with pyrrole (3) in the construction of polyheterocyclic frame-
works. Appropriate combinations of such processes when used
in conjunction with differing tethers for connection of the
reacting centres should allow for the rapid assembly of a diverse
array of multiply-fused pyrroles and pyrrolidines. In addition,
the development of enantioselective variants of conversions
such as 10
11 would serve to further enhance the value of
the strategies described here. Recent work by McMillan18 on
enantioselective and intermolecular Friedel–Crafts alkylations
of pyrroles suggests that such variants are possible and these
are being pursued in our laboratories at present. Results will be
reported in due course.
Experimental
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
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
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
J. Chem. Soc., Perkin Trans. 1, 2002, 2613–2618
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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 the data are given as:
chemical shift (δ) (protonicity), where protonicity is defined as:
6-(1H-Pyrrol-1-yl)hexan-3-one (9)
Ethyl magnesium bromide (13.33 mL of a 3 M solution in
diethyl ether, 40 mmol) was slowly added to a magnetically
stirred solution of amide 8 (5.00 g, 24 mmol) in diethyl ether
(150 mL) maintained at 0 ЊC under a nitrogen atmosphere. The
cooling bath was then removed and the reaction mixture stirred
at 18 ЊC for 2 h before being cooled to Ϫ40 ЊC and treated,
dropwise, with potassium hydrogensulfate (10 mL of a 0.3 M
aqueous solution). After 5 min sodium bicarbonate (10 mL of a
2 M aqueous solution) was slowly added and the resulting mix-
ture warmed to 18 ЊC then diluted with brine (50 mL). The
separated aqueous phase was extracted with ether (2 × 25 mL)
and the combined organic phases then dried, filtered and con-
centrated under reduced pressure to give the title ketone 94
(3.96 g, 100%) as a clear colourless oil. νmax (KBr, neat) 1713
cmϪ1; δH (CD3COCD3) 1.07 (3H, t, J 7), 2.07 (2H, quin, J 7),
2.50, (4H, m), 4.02, (2H, t, J 7), 6.14 (2H, m), 6.62 (2H, m); m/z
165 (Mϩ, 100%), 148 (15), 136 (30), 108 (35), 99 (45), 81 (55).
This unstable material was used immediately in the next step of
the reaction sequence as described in the following paragraph.
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.
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 per-
manganate 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-workers19 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 inter-
mediates were carried out under an atmosphere of dry, oxygen-
free nitrogen.
Methyl 3-ethyl-6-(1H-pyrrol-1-yl)hex-2-enoate (10)
Methyl diethylphosphonoacetate (4.10 g, 22.5 mmol) was
added dropwise to a magnetically stirred suspension of NaH
(612 mg, 25.5 mmol) in THF (30 mL) maintained at 0 ЊC under
a nitrogen atmosphere. The cooling bath was then removed and
the ensuing mixture stirred for 15 min at 18 ЊC then treated,
dropwise, with a solution of ketone 9 (2.10 g, 12.75 mmol) in
THF (5 mL). The reaction mixture was stirred at 18 ЊC for 48 h
then diluted with brine (20 mL) and extracted with diethyl ether
(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 concen-
tration of the appropriate fractions, the title compound 104
(2.17 g, 77%) as a clear colourless oil and which was comprised
of a ca. 1:1 mixture of E/Z isomers as judged by H NMR
analysis. This material was used directly in the next step of the
reaction sequence.
For the purposes of characterization, a small sample of
compound 10 was subject flash chromatography (silica gel, 5:95
v/v ethyl acetate–hexane elution) and in this way two fractions,
A and B, were obtained.
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 mix-
tures were dried with magnesium sulfate (MgSO4). Organic
solutions were concentrated under reduced pressure on a rotary
evaporator with the water bath generally not exceeding 40 ЊC.
1
Concentration of fraction A (Rf 0.3 in 1:9 v/v ethyl acetate–
N-Methoxy-N-methyl-4-(1H-pyrrol-1-yl)butanamide (8)
hexane) afforded (E)-10 as a clear colourless oil (Found: Mϩ
,
ؒ
221.1414. C13H19NO2 requires Mϩ , 221.1416); νmax (KBr, neat)
3100, 2968, 1714, 1644, 1164, 723 cmϪ1; δH 1.07 (3H, t, J 7), 1.93
(2H, m), 2.16 (2H, dq, J 7 and 1.4), 2.61 (2H, m), 3.69 (3H, s),
3.94 (2H, t, J 7), 5.68 (1H, s), 6.15 (2H, t, J 2), 6.68 (2H, t, J 2);
δC 12.0, 29.7, 30.5, 31.1, 49.6, 50.9, 107.9, 114.5, 120.4, 164.7,
166.9; m/z 221 (Mϩ, 35%), 206 (27), 190 (45), 162 (80), 160 (42),
148 (45), 94 (43), 81 (100).
ؒ
Triethylamine (7.08 g, 70 mmol) was added slowly to a mag-
netically stirred suspension of N,O-dimethylhydroxylamine
hydrochloride (6.825 g, 70 mmol) in CH2Cl2 (150 mL) main-
tained at 0 ЊC under a nitrogen atmosphere. The cooling bath
was then removed and after 15 min acid 79 (10.0 g, 65.3 mmol)
and pyridine N-oxide disulfide (24.57 g, 97.5 mmol) were
added. The reaction mixture was re-cooled to 0 ЊC then, whilst
protected from light, tributylphosphine (19.73 g, 97.5 mmol)
was added slowly. The ensuing mixture was allowed to warm to
18 ЊC, stirred at this temperature for 16 h then concentrated
under reduced pressure. The residue was diluted with ethyl
acetate (200 mL), washed with potassium hydrogensulfate
(2 × 50 mL of a 0.3 M aqueous solution), sodium bicarbonate
(2 × 50 mL of a 2 M aqueous solution) then dried, filtered and
concentrated under reduced pressure to give a light-yellow oil.
This material was passed down a short column of silica gel
(3:7 v/v ethyl acetate–hexane elution) to give, after concen-
tration of the filtrate, compound 84,10 (11.1 g, 87%) as a clear,
Concentration of fraction B (Rf 0.25 in 1:9 v/v ethyl acetate–
hexane) afforded (Z)-10 as a clear colourless oil (Found Mϩ
,
ؒ
221.1415. C13H19NO2 requires Mϩ , 221.1416); νmax (KBr, neat)
3100, 2948, 1716, 1644, 1149, 724 cmϪ1; δH 1.06 (3H, t, J 7.5),
1.95 (2H, m), 2.14 (2H, m), 2.62 (2H, q, J 7.5), 3.69 (3H, s), 3.90
(2H, t, J 6.9), 5.62 (1H, s), 6.06 (2H, t, J 2.1), 6.65 (2H, t, J 2.1);
δC 13.0, 25.2, 29.2, 34.7, 48.8, 50.9, 108.1, 114.9, 120.4, 164.5,
166.6; m/z 221 (Mϩ, 30%), 206 (5), 192 (25), 162 (65), 148 (50),
94(38), 81 (100).
ؒ
Methyl 8-ethyl-5,6,7,8-tetrahydroindolizine-8-acetate (11)
colourless oil (Found: Mϩ , 196.1211. C10H16N2O2 requires
ؒ
Mϩ , 196.1212); νmax (KBr, neat) 1660 cmϪ1; δH 2.09 (2H, quin,
Anhydrous aluminium chloride (815 mg, 6.1 mmol) was added,
in small portions, to a magnetically stirred solution of the
α,β-unsaturated ester 10 (270 mg, 1.22 mmol) in diethyl ether
(20 mL) maintained at 0 ЊC under a nitrogen atmosphere. The
resulting mixture was stirred at 18 ЊC for 5 h then re-cooled to
ؒ
J 7), 2.36 (2H, t, J 7), 3.16 (3H, s), 3.60 (3H, s), 3.96 (2H, t, J 7),
6.13 (2H, t, J 2.1), 6.65 (2H, t, J 2.1); δC 26.1, 28.3, 31.9, 48.5,
61.0, 107.9, 120.5, 173.4; m/z 196 (Mϩ, 70%), 165 (30), 136
(100), 118 (30), 106 (35), 80 (60).
2616
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(949 mg, 91%) as a clear colourless oil (Found: Mϩ , 202.1467.
ؒ
0 ЊC and slowly treated (CAUTION) with water (10 mL) fol-
lowed by sulfuric acid (20 mL of a 0.5 M aqueous solution).
The separated aqueous phase was extracted with diethyl ether
(1 × 20 mL) and the combined organic phases then dried, fil-
C13H18N2 requires Mϩ , 202.1470); νmax (KBr, neat) 2934, 2244,
ؒ
1459, 714 cmϪ1; δH 0.86 (3H, t, J 7.3), 1.58–1.78 (4H, complex
m), 1.91–2.04 (4H, complex m), 2.26 (2H, m), 3.89 (2H, t,
J 6.0), 5.83 (1H, dd, J 3.6 and 1.8), 6.12 (1H, dd, J 3.6 and 2.7),
6.52 (1H, dd, J 2.7 and 1.8); δC 8.4, 12.8, 19.9, 30.4, 33.0, 35.2,
37.6, 45.1, 104.2, 107.4, 119.2, 120.4, 133.0; m/z 202 (Mϩ, 40%),
173 (100), 148 (70), 133 (45), 118 (20).
tered and concentrated under reduced pressure to give com-
pound 114 (223 mg, 83%) as a clear colourless oil (Found: Mϩ
,
ؒ
221.1414. C13H19NO2 requires Mϩ , 221.1416); νmax (KBr, neat)
2942, 1732, 706 cmϪ1; δH (CD3COCD3) 0.94 (3H, t, J 7.5), 1.81–
1.96 (3H, complex m), 2.04–2.15 (3H, complex m), 2.67 (2H,
m), 3.66, (3H, s), 3.99 (2H, m), 5.90 (1H, dd, J 3.7 and 1.7), 6.06
(1H, m), 6.57 (1H, m); δC (CD3COCD3) 8.6, 20.2, 30.5, 33.0,
37.6, 44.6, 45.1, 50.6, 103.9, 107.2, 118.7, 134.1, 171.5; m/z 221
(Mϩ, 43%), 206 (6), 192 (70), 160 (8), 148 (100), 132 (82), 118
(17).
ؒ
3-(8-Ethyl-5,6,7,8-tetrahydroindolizin-8-yl)propionic acid (15)
A magnetically stirred solution nitrile 14 (274 mg, 1.35 mmol)
and KOH (2.00 g, 35.6 mmol) in aqueous methanol (7 mL of a
4:3 v/v mixture) was heated at reflux for 16 h. The cooled mix-
ture was then acidified with HCl (conc. aqueous solution) and
extracted with CH2Cl2 (4 × 20 mL). The combined organic
phases were then dried, filtered and concentrated under reduced
2-(8-Ethyl-5,6,7,8-tetrahydroindolizin-8-yl)ethanol (12)
pressure to give the acid 15 (262 mg, 88%) as a light-yellow oil
DIBAL-H (1.95 mL of a 1 M solution in hexane, 1.95 mmol)
was added, dropwise, to a magnetically stirred solution of ester
11 (180 mg, 0.84 mmol) in CH2Cl2 (10 mL) and maintained at
Ϫ78 ЊC under a nitrogen atmosphere. The resulting solution
was stirred at Ϫ78 ЊC for a further 30 min, warmed to 0 ЊC,
stirred at this temperature for 1 h then quenched with water
(10 mL) and extracted with CH2Cl2 (2 × 10 mL). The combined
organic phases were dried, filtered and concentrated under
reduced pressure to give a light-yellow oil. This material was
subject to flash chromatography (silica gel, 2:3 v/v ethyl acetate–
hexane elution) and concentration of the appropriate fractions
ϩ
(Found: Mϩ , 221.1417. C13H19NO2 requires M , 221.1416);
νmax (neat) 2942, 1705 cmϪ1; δH 0.86 (3H, t, J 7.3), 1.67 (4H, m),
1.91 (2H, m), 1.99 (2H, m), 2.33 (2H, m), 3.89 (2H, t, J 6.0),
5.87 (1H, dd, J 3.6 and 1.8), 6.12 (1H, dd, J 3.6 and 2.7), 6.50
(1H, dd, J 2.7 and 1.8), 11.0 (1H, br s); δC 8.5, 20.0, 29.8, 30.7,
33.2, 34.2, 37.3, 45.3, 104.2, 107.2, 118.7, 134.5, 180.7; m/z 221
(Mϩ, 50%), 192 (90), 174 (15), 148 (100), 133 (35), 118 (25).
ؒ
ؒ
6a-Ethyl-4,5,6,6a,7,8-hexahydro-9H-pyrrolo[3,2,1-i,j]quinolin-
9-one (16)
afforded the alcohol 12 (122 mg, 75%) as a clear, colourless
A magnetically stirred solution of the acid 15 (189 mg, 0.81
mmol) in HCl (5 mL of a 5 M aqueous solution) was main-
tained at 18 ЊC for 1 h then made alkaline by the addition of
Na2CO3 (saturated aqueous solution) and 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 flash chromatography
(silica gel, ether elution) and concentration of the appropriate
ϩ
oil (Found: Mϩ , 193.1468. C12H19NO requires M , 193.1467);
ؒ
ؒ
νmax (KBr, neat) 3367, 2936, 1462, 1325, 1028, 707 cmϪ1
;
δH (CD3OD) 0.82 (3H, t, J 7.5), 1.60 (2H, m), 1.71 (2H, m), 1.81
(2H, m), 1.94 (2H, m), 3.53 (2H, m), 3.84 (2H, dt, J 6.0 and 1.8),
5.78 (1H, dd, J 3.6 and 1.8), 5.99 (1H, dd, J 3.6 and 2.7), 6.45
(1H, dd, J 2.7 and 1.8); δC 8.6, 20.1, 31.0, 33.8, 36.7, 42.4, 45.3,
59.7, 103.5, 107.3, 118.8, 135.4; m/z 193 (Mϩ, 50%), 164 (100),
148 (90), 134 (40), 118 (25).
fractions afforded ketone 16 (118 mg, 72%) as a clear, colourless
ϩ
oil (Found: Mϩ , 203.1308. C13H17NO requires M , 203.1310);
ؒ
ؒ
νmax (KBr, neat) 2942, 1652, 1513, 1466, 1314, 1188 cmϪ1
;
2-(8-Ethyl-5,6,7,8-tetrahydroindolizin-8-yl)ethyl methane-
sulfonate (13)
δH 0.90 (3H, t, J 7.2), 1.31 (1H, td, J 13.5 and 3.3) 1.71 (3H, m),
1.99–2.01 (1H, complex m), 2.05 (1H, dt, J 13.5 and 3.3), 2.11–
2.28 (2H, complex m), 2.38 (1H, ddd, J 18.0, 4.8 and 2.1), 2.65
(1H, ddd, J 18.0, 13.5 and 4.8), 3.77 (1H, td, J 11.7 and 6.3),
4.03 (1H, ddd, J 12.6, 6.9 and 1.5) 6.50 (2H, apparent q, J 2.7);
δC 8.7, 18.5, 26.8, 28.3, 33.8, 35.0, 43.9, 106.3, 116.9, 121.8,
151.1, 193.8 (one signal due to pyrrolic carbon obscured or
overlapping); m/z 203 (Mϩ, 40%), 174 (100), 160 (10), 146 (25).
Methanesulfonyl chloride (687 mg, 6 mmol) was added, drop-
wise, to a magnetically stirred solution of alcohol 12 (1.124 g,
5.79 mmol) and triethylamine (607 mg, 6 mmol) in CH2Cl2
(50 mL) maintained at 0 ЊC under a nitrogen atmosphere. The
resulting mixture was stirred for 5 min at 0 ЊC, for 45 min at
18 ЊC then washed with Na2CO3 (2 × 50 mL of a 2 M aqueous
solution) and HCl (2 × 50 mL of 2 M aqueous solution) before
being dried, filtered and concentrated under reduced pressure
(6aꢀ,9aꢀ,9bꢀ)-6a-Ethyldecahydro-4H-pyrrolo[3,2,1-i,j]quinoline
(18) and (6aꢀ,9aꢁ,9bꢁ)-6a-ethyldecahydro-4H-pyrrolo[3,2,1-i,j]-
quinolin-9-one (19)
to give the mesylate 13 (1.491 g, 95%) as a light-yellow oil
ϩ
(Found: Mϩ , 271.1241. C13H21NO3S requires M , 271.1242);
νmax (KBr, neat) 2938, 1696, 1353, 1173, 950 cmϪ1; δH 0.86 (3H,
t, J 7.3), 1.58–1.76 (4H, complex m), 1.94–2.07 (4H, complex
m), 2.93 (3H, s), 3.88 (2H, t, J 6.0), 4.23 (2H, m), 5.86 (1H, dd,
J 3.6 and 1.8), 6.10 (1H, dd, J 3.6 and 2.7), 6.49 (1H, dd, J 2.7
and 1.8); δC 8.6, 20.1, 31.1, 33.8, 36.9, 37.3, 38.5, 45.2, 68.0,
104.2, 107.4, 118.9, 133.7; m/z 271 (Mϩ, 40%), 242 (50), 148
(90), 146 (100), 133 (30), 118 (25).
ؒ
ؒ
A magnetically stirred solution of ketone 16 (35 mg, 0.172
mmol) in acetic acid (7 mL) and containing PtO2 (10 mg)
was maintained at 18 ЊC under an atmosphere of hydrogen
(balloon) for 18 h. The resulting mixture was filtered through a
plug of Celite and the filtrate concentrated under reduced
pressure. A magnetically stirred solution of the resulting oil
(containing alcohol 17 and the corresponding deoxy-analogue
18) in CH2Cl2 (5 mL) was cooled to 0 ЊC then treated with the
Dess–Martin periodinane15 (220 mg, 0.516 mmol). Stirring was
continued at 0 ЊC for 30 min and at 18 ЊC for 30 min then the
reaction mixture was treated with NaHCO3 (5 mL of a satur-
ated aqueous solution) and Na2S2O3 (5 mL of a 20% w/v aque-
ous solution). The ensuing mixture was stirred rapidly at 18 ЊC
for 15 min then the separated aqueous phase was extracted with
CH2Cl2 (3 × 10 mL). The combined organic extracts were dried
(sodium sulfate), filtered and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material to
flash chromatography (silica gel, 200:180:19:1 v/v/v/v CH2Cl2–
CHCl3–MeOH–NH3 elution) afforded two fractions A and B.
3-(8-Ethyl-5,6,7,8-tetrahydroindolizin-8-yl)propionitrile (14)
Sodium cyanide (1.225 g, 25 mmol) was added to a magnetic-
ally stirred solution of the mesylate 13 (1.40 g, 5.16 mmol) in
DMPU (10 mL) maintained at 18 ЊC under a nitrogen atmos-
phere. The ensuing mixture was stirred at this temperature for
48 h then diluted with water (50 mL) and extracted with ethyl
acetate (3 × 25 mL). The combined organic phases were then
dried, filtered and concentrated under reduced pressure to give
a light-yellow oil. Subjection of this material to flash chrom-
atography (silica gel, 1:4 v/v ethyl acetate–hexane elution)
gave, after concentration of the appropriate fractions, nitrile 14
J. Chem. Soc., Perkin Trans. 1, 2002, 2613–2618
2617

View Article Online
Concentration of fraction A afforded amine 18 (7 mg, 22%)
as a clear, colourless oil. νmax (KBr, neat) 1619, 1425 cmϪ1
complex m), 2.73 (1H, m), 3.13 (2H, m); δC 7.8, 17.6, 19.8, 21.9,
32.9, 34.7, 35.7, 39.0, 48.6, 53.6, 54.2, 76.8, 209.4; m/z 207 (Mϩ,
30%), 206 (100), 177 (10).
;
δH (600 MHz, CD3OD) 0.84 (3H, t, J 7.5), 1.11–1.38 (6H, com-
plex m), 1.45–1.62 (6H, complex m), 1.66–1.92 (4H, complex
m), 2.02 (1H, m), 2.08 (1H, m), 3.03 (1H, m), 3.10 (1H, td, J 9.0
and 3.3); δC (150 MHz, CD3OD) 7.2, 22.0, 22.8, 26.7, 29.3, 31.0,
31.9, 35.3, 35.4, 35.8, 54.4, 54.5, 73.1; m/z 193 (Mϩ, 30%), 192
(100), 178 (5), 164 (35).
Acknowledgements
We thank the Institute of Advanced Studies for financial sup-
port including the provision of a Post-Doctoral Fellowship to
JAS. Professor J. Aubé (University of Kansas) is thanked for
providing copies of the 1H and 13C NMR spectra of ketone 19.
Concentration of fraction B afforded ketone 198o (8 mg,
ϩ
ؒ
28%) as a clear, colourless oil [Found: (M Ϫ H ) , 206.1547,
ϩ
ؒ
C13H21NO requires (M – H ) , 206.1545]; νmax (KBr, neat) 2932,
1708 cmϪ1; δH (600 MHz) 0.93 (3H, t, J 7.5), 1.10 (1H, m), 1.31
(2H, m), 1.46–1.52 (2H, complex m), 1.59–1.97 (7H, complex
m), 2.18–2.48 (3H, complex m), 2.66 (1H, ddd, J 9.0, 5.4 and
2.1), 3.00 (2H, m); δC (150 MHz) 7.1, 21.3, 26.0, 29.7, 30.1, 32.8,
34.7, 36.8, 48.1, 52.9, 53.2, 73.5, 211.7; m/z 207 (Mϩ, 50%), 206
(100), 178 (50), 150 (15), 124 (25), 95 (20), 82 (35).
References
1 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.
2 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.
3 M. G. Banwell, A. M. Bray, A. C. Willis and D. J. Wong,
New J. Chem., 1999, 23, 687.
( )-6a-Ethyl-1,2,4,5,6,6a,7,8-octahydro-9H-pyrrolo[3,2,1-i,j]-
quinolin-9-one (21)
A magnetically stirred solution of ketone 16 (25 mg, 0.123
mmol) in acetic acid–ethanol (20 mL of a 2:98 v/v mixture)
containing 5% Rh/Al2O3 (∼10 mg) was maintained at 18 ЊC
under an atmosphere of hydrogen (balloon) for 18 h. The
resulting mixture was filtered through a plug of Celite and
the filtrate concentrated under reduced pressure to give a
light-yellow oil. Subjection of this material to flash chrom-
atography (silica gel, successive elution with 3:2 v/v ethyl
acetate–hexane then 180:19:1 v/v/v CHCl3–MeOH–NH3)
afforded two fractions, A and B.
4 M. Banwell, A. Edwards, J. Smith, E. Hamel and P. Verdier-Pinard,
J. Chem. Soc., Perkin Trans. 1, 2000, 1497.
5 See: O. Baudoin, M. Cesario, D. Guénard and F. Guéritte,
J. Org. Chem., 2002, 67, 1199 and references cited therein.
6 For
a recent review see: J. E. Saxton in The Alkaloids,
ed. G. A. Cordell, Academic Press, New York, 1998, vol. 51,
pp. 1–197.
7 G. Stork and J. E. Dolfini, J. Am. Chem. Soc., 1963, 85, 2872.
8 (a) A. Camerman, N. Camerman, J. P. Kutney and J. Trotter,
Tetrahedron Lett., 1965, 637; (b) J. Harley-Mason and M. Kaplan,
J. Chem. Soc., Chem. Commun., 1967, 915; (c) J. Y. Laronze,
J. Laronze-Fontaine, J. Levy and J. Le Men, Tetrahedron Lett., 1974,
491; (d ) Y. Ban, K. Yoshida, J. Goto and T. Oishi, J. Am. Chem.
Soc., 1981, 103, 6990; (e) T. Gallagher, P. Magnus and J. Huffman,
J. Am. Chem. Soc., 1982, 104, 1140; ( f ) S. B. Mandal, V. S. Giri,
M. S. Sabeena and S. C. Pakrashi, J. Org. Chem., 1988, 53, 4236;
(g) A. I. Myers and D. Berney, J. Org. Chem., 1989, 54, 4673;
(h) M. Node, H. Nagasawa and K. Fuji, J. Org. Chem., 1990,
55, 517; (i) P. Le Menez, N. Kunesch, S. Liu and E. Wenkert,
J. Org. Chem., 1991, 56, 2915; (j) D. Desmaële and J. d’Angelo,
J. Org. Chem., 1994, 59, 2292; (k) E. Wenkert and S. Liu,
J. Org. Chem., 1994, 59, 7677; (l ) P. Forns, A. Diez and
M. Rubiralta, J. Org. Chem., 1996, 61, 7882; (m) A. G. Schultz and
L. Pettus, J. Org. Chem., 1997, 62, 6855; (n) O. Callaghan,
C. Lampard, A. R. Kennedy and J. A. Murphy, J. Chem. Soc.,
Perkin Trans. 1, 1999, 995; (o) R. Iyengar, K. Schildknegt and
J. Aubé, Org. Lett., 2000, 2, 1625; (p) M. A. Toczko and
C. H. Heathcock, J. Org. Chem., 2000, 65, 2642; (q) B. Patro
and J. A. Murphy, Org. Lett., 2000, 2, 3599; (r) S. A. Kozmin, T.
Iwama, Y. Huang and V. H. Rawal, J. Am. Chem. Soc., 2002, 124,
4628.
Concentration of fraction A afforded the starting ketone 16
(12 mg, 50% recovery) which was identical, in all respects, with
an authentic sample.
Concentration of fraction B afforded compound 21 (10 mg,
80% at 50% conversion) as a clear colourless oil (Found: Mϩ
,
ؒ
205.1465. C13H19NO requires Mϩ , 205.1467); νmax (neat) 2934,
1562, 1515 cmϪ1; δH 0.87 (3H, t, J 7.5), 1.12 (1H, td, J 13.5 and
3.3), 1.46–2.00 (7H, complex m), 2.25 (1H, ddd, J 17.4, 5.4 and
2.1), 2.43 (1H, ddd, J 17.4, 13.5 and 4.8), 2.60 (1H, m), 2.78
(2H, m), 3.17 (1H, q, J 10.5), 3.28 (1H, dd, J 11.4 and 5.4), 3.58
(1H, ddd, J 11.4, 10.5 and 4.0); δC 7.8, 18.6, 23.9, 25.2, 28.5,
32.4, 33.2, 35.0, 46.9, 54.0, 107.4, 175.8, 190.0; m/z 205 (Mϩ,
45%), 177 (90), 162 (100), 148 (17), 135 (16).
ؒ
(6aꢀ,9aꢀ,9bꢀ)-6a-Ethyldecahydro-4H-pyrrolo[3,2,1-i,j]quinolin-
9-one (22)
A solution of the dihydropyrrole 21 (18 mg, 0.09 mmol) in THF
(0.5 mL) was slowly added to a magnetically stirred suspension
of LiAlH4 (excess) in THF (5 mL) maintained at 18 ЊC under an
nitrogen atmosphere. The resulting mixture was heated at reflux
for 1.5 h then cooled, treated with ethyl acetate (2 mL) then
water (5 mL) and finally extracted with CH2Cl2 (3 × 10 mL).
The combined organic extracts were dried (sodium sulfate),
filtered and concentrated under reduced pressure to give a
light-yellow oil. Subjection of this material to flash chromato-
graphy (silica gel, 180 : 19 : 1 v/v/v CHCl3–MeOH–NH3 elu-
tion) afforded, after concentration of the appropriate fractions,
ketone 2216 (12 mg, 65%) as a clear, colourless oil [Found:
9 J.-H. Li and J. K. Snyder, J. Org. Chem., 1993, 58, 516.
10 M. Banwell and J. Smith, Synth. Commun., 2001, 31, 2011.
11 M. G. Banwell, B. D. Bissett, C. Bui, H. T. T. Pham and
G. W. Simpson, Aust. J. Chem., 1998, 51, 9.
12 See, for example: R. Lueoend and R. Neier, Helv. Chim. Acta, 1991,
74, 91–102 and references cited therein.
13 R. K. Crossland and K. L. Servis, J. Org. Chem., 1970, 35, 3195.
14 (a) T. Mukhopadhyay and D. Seebach, Helv. Chim. Acta, 1982, 65,
385; (b) M. Banwell, A. Edwards, J. Harvey, D. Hockless and
A. Willis, J. Chem. Soc., Perkin Trans. 1, 2000, 2175.
15 R. E. Ireland and L. Liu, J. Org. Chem., 1993, 58, 2899.
16 Y. Ban, I. Iijima, I. Inoue, M. Akagi and T. Oishi, Tetrahedron Lett.,
1969, 2067.
ϩ
ϩ
17 G. Lawton, J. E. Saxton and A. J. Smith, Tetrahedron, 1977, 33,
ؒ
ؒ
(M Ϫ H ) , 206.1547, C13H21NO requires (M Ϫ H ) ,
206.1545]; νmax (KBr, neat) 2933, 1717 cmϪ1; δH 0.73 (1H, m),
0.89 (3H, t, J 7.5), 1.12 (1H, tdd, J 13.2, 5.1 and 1.5), 1.44–1.84
(7H, complex m), 1.89–2.04 (4H, complex m), 2.21–2.42 (2H,
1641.
18 N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2001, 123,
4370.
19 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
2618
J. Chem. Soc., Perkin Trans. 1, 2002, 2613–2618