Synthesis of ABE tricyclic analogues of methyllycaconitine using a Wacker oxidation-aldol strategy to append the B ring to the AE fragment

Article abstract of DOI:10.1039/b200073n

The synthesis of ABE tricyclic analogues 18 of the alkaloid methyllycaconitine 1 is described. The analogues contain the key pharmacophore reputed to be responsible for the biological activity of methyllycaconitine 1, namely, a homocholine motif formed fr

Full text of DOI:10.1039/b200073n

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Synthesis of ABE tricyclic analogues of methyllycaconitine using
a Wacker oxidation–aldol strategy to append the B ring to the
AE fragment
1
David Barker,a Margaret A. Brimble,*b Malcolm McLeod,*a G. Paul Savagec
and David J. Wonga
a School of Chemistry, F11University of Sydney, Camperdown, NSW 2006, Australia
b Department of Chemistry, University of Auckland, Private Bag 92019, Auckland,
New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: ϩ64 9 3737422
c CSIRO Molecular Science, Bag 10, Clayton South, Vic. 3169, Australia
Received (in Cambridge, UK) 3rd January 2002, Accepted 14th February 2002
First published as an Advance Article on the web 27th February 2002
The synthesis of ABE tricyclic analogues 18 of the alkaloid methyllycaconitine 1 is described. The analogues
contain the key pharmacophore reputed to be responsible for the biological activity of methyllycaconitine 1,
namely, a homocholine motif formed from a tertiary N-ethylamine in a 3-azabicyclo[3.3.1]nonane ring system and
a 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester side chain. The 3-azabicyclo[3.3.1]nonane ring system 10 was
assembled via a double Mannich reaction of ethyl 3-(but-3Ј-enyl)-2-oxocyclohexane-1-carboxylate 9 with ethylamine
and formaldehyde. Attempts to append a B ring to this AE ring system via McMurray coupling of dialdehyde 5 were
hampered by the inability to effect conversion of the C-9 ketone 10 to vinyl ether 6. Wittig methylenation of ketone
10 afforded diene 7, however, subsequent attempts to effect double hydroboration–oxidation of diene 7 failed to
realise diol 11 en route to the key dialdehyde precursor 5 required for the McMurray coupling. Wacker oxidation
of the homoallyl group of 10 afforded methyl ketone 12 which underwent intramolecular aldol condensation
to form enone 13. After selective reduction of the ketone and methylation, the resultant methyl ethers 15
underwent reduction of the ester sidechain affording neopentyl substituted alcohols 16. Finally, the
2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester sidechain was appended by treatment of alcohols
16 with N-(trifluoroacetyl)anthranilic acid followed by fusion of the resultant anthranilates 17 with
methylsuccinic anhydride.
neuronal α7 subtype nAChRs than its substituted anthranilate
Introduction
ester methyllycaconitine 1.5 The high toxicity of methyl-
Methyllycaconitine 1 is the principle toxin in Delphinium
lycaconitine 1 to mammals prevents its use as an agrochemical,
brownii,1 a cattle-stock poison in Western Canada, and is also
found in at least 30 Delphinium species as well as in Consolida
however, if the inhibitory action of methyllycaconitine 1 is
localised in a small toxophoric section of the molecule, a sub-
ambigua and Inaularoyaleana.2,3 Both its toxicity and insecti-
unit of methyllycaconitine 1 based on this section, may have the
cidal activity have been attributed to its ability to act as a potent
desired toxophoric properties yet be significantly lower in
inhibitor of the nicotinic acetylcholine receptor (nAChR) bind-
toxicity towards mammals. Therefore interest in synthesizing
ing in mammalian and insect neural membranes.4 At the α-7
analogues of methyllycaconitine 1 as lead compounds for the
development of new insecticides continues.
The N-substituted anthranilate ester moiety is considered an
subtype of nAChR, methyllycaconitine 1 is among the most
potent, small molecule competitive antagonists yet reported.5
essential structural feature for insecticidal and pharmacological
activity. It has also been proposed that at physiological pH
the tertiary amine in the homocholine motif embedded in the
AF rings of methyllycaconitine 1 is protonated and therefore
mimics acetylcholine, and that the (S)-methylsuccinimido ring
may help to maintain the correct geometry between the tertiary
nitrogen atom of the F ring in the alkaloid and the carbonyl
oxygen of the ester bond.7 We therefore herein report the syn-
thesis of tricyclic analogues of methyllycaconitine 18 contain-
ing the key 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester in
which an additional six membered ring (a B ring) is appended
to a 3-azabicyclo[3.3.1]nonane framework (the AE rings). It
was envisaged that incorporation of the N-substituted anthran-
ilate ester and the N-ethyl group embedded in the homo-
choline motif, into a conformationally restricted framework
Methyllycaconitine 1 is the 2-[2-(S)-methylsuccinimido]-
benzoate ester of the norditerpenoid alkaloid lycoctonine 2.6
Lycoctonine 2, however, exhibits 2000 times less affinity for rat
may enhance the biostability, selectivity and potency of simpler
bicyclic AE analogues of methyllycaconitine 1 that had been
prepared previously.
924
J. Chem. Soc., Perkin Trans. 1, 2002, 924–931
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b200073n

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Methyllycaconitine 1 has not succumbed to total synthesis,
however, a semi-synthesis of methyllycaconitine 1 from its
parent alkaloid lycoctonine 2 has been reported by Blagbrough
and co-workers8 which established the absolute configuration
of the methylsuccinimide moiety to be S. Alternative semi-
syntheses of methyllycaconitine 1 from lycoctonine 2 used a
2-(N-succinimido)benzoic acid to append the anthranilate ester
moiety to a neopentyl alcohol.9
ester 8 was treated with NaH to generate the sodium enolate
followed by the addition of butyllithium at 0 ЊC in dry THF to
generate the dianion. Subsequent addition of 4-bromobut-1-
ene and warming the reaction mixture to room temperature
afforded the desired butenyl-substituted keto ester 9 in 83%
yield (Scheme 2). The 1H NMR spectrum of the product 9 was
in agreement with the literature.17
Simple E ring analogues of methyllycaconitine 1 contain-
ing the homocholine motif have been prepared by Bergmeier
et al.10 containing a piperidine ring substituted at C-3 with
a 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester. AE bi-
cyclic analogues of methyllycaconitine 1 have been prepared by
Blagbrough and co-workers11 in which the 3-azabicyclo[3.3.1]-
nonane framework was assembled via a double Mannich reac-
tion using 2-oxocyclohexane-1-carboxylate, ethylamine and
formaldehyde. The azabicyclo[3.3.1]nonane bicyclic skeleton
was then extended from the ketone at C-5 by the addition of
Grignard, Wittig and alkyllithium reagents.12
To date the main attention for the synthesis of tricyclic ana-
logues of methyllycaconitine 1 has been focused on assembly of
AEF analogues. One approach by Kraus and Dneprovskaia13
involved carrying out a similar Mannich reaction on a spiro-
cyclic enone whereas Whiting and co-workers14 formed the
azabicyclic system via condensation of an ester with an amine
formed by reduction of a nitrone that in turn had been formed
by oxidative cleavage of an isoxazolidine. The work reported
herein provides methodology for the synthesis of the first
examples of tricyclic analogues of methyllycaconitine 1 that
contain an ABE framework. The synthetic work reported
herein was prompted by a report that an ABE tricyclic analogue
of methyllycaconitine 1 was more potent than an AE bicyclic
analogue, however, the synthesis and characterisation of the
ABE tricyclic analogue was not described.15
Scheme 2 Reagents, conditions and yields: (i) NaH, THF (2.0 equiv.),
0 ЊC, 10 min, then BuLi (1.6 equiv.), 0 ЊC, 25 min, 4-bromobut-1-ene,
0 ЊC, 2 h then room temp., 20 h (83%) (ii) EtNH2, H2CO, EtOH, reflux,
24 h (41%) (iii) Ph3PϩCH3BrϪ (4.0 equiv.), BuLi (3.0 equiv.), THF,
refux, 24 h (85%).
Results and discussion
Initial synthetic effort was directed towards the synthesis of
ABE tricyclic analogue 3 which contains a dihydroxylated seven
membered B ring (Scheme 1). Our synthetic strategy to prepare
With butenyl-substituted keto ester 9 in hand, attention then
turned to the formation of the azabicyclic ring system present
in the AE rings of methyllycaconitine 1. Keto ester 9 was heated
under reflux with one equivalent of ethylamine and two equiv-
alents of formaldehyde in ethanol for 24 h to afford Mannich
product 10 in 41% yield. The moderate yield obtained for this
step is consistent with reports in the literature that state that
double Mannich reactions using cyclohexanones that are sub-
stituted with only one carboxylate group at the α position such
as keto ester 9, proceed in much lower yield than analogous
reactions carried out using more highly activated cyclohex-
anones that are substituted with esters at both the α and αЈ
positions.18 This is due to the low reactivity of the alternative
αЈ carbon in β keto ester 9 (i.e. C-6) relative to the highly acidic
α-position (C-2).
Elemental analysis of 10 was consistent with the required
formula C17H27NO3. In the 1H NMR spectrum 7A-H character-
istically resonated at δH 2.86–2.98 further downfield than 7B-H
due to the deshielding influence of the nearby nitrogen lone
pair. This feature of the spectrum together with the long range
W-coupling observed between 2A-H and 4A-H (J2A,4A 2.2 Hz)
were consistent with formation of the 3-azabicyclo[3.3.1]-
nonane ring system (Fig. 1).19 The large upfield shift of 2B-H
(δH 2.86–2.98) and 4B-H (δH 2.55) compared to their geminal
protons 2A-H and 4A-H respectively, is attributed to the over-
lap of the nitrogen lone pair with the adjacent trans-coplanar
C–H anti-bonding orbitals.
Scheme 1
analogue 3 hinged on the use of a McMurray coupling to
assemble diol 4 from dialdehyde 5. It was envisaged that the
butyraldehyde side chain in dialdehyde 5 would be formed via
hydroboration of an alkene and that the second aldehyde group
could be generated via hydrolysis of enol ether 6. In turn enol
ether 6 was available via Wittig olefination of ketone 10.
The proposed conversion of azabicyclo[3.3.1]nonane 10 to
ABE analogue 4 required initial preparation of dialdehyde
5 proceeding by way of methyl vinyl ether 6. Unfortunately,
Homoallylation of β-keto ester 8 was performed efficiently
using the method reported by Huckin and Weiler.16 Thus β-keto
J. Chem. Soc., Perkin Trans. 1, 2002, 924–931
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Fig. 1 Characteristic features in the 1H NMR spectrum of 10.
attempts to effect Wittig olefination of ketone 10 with meth-
oxymethyltriphenylphosphonium chloride using either butyl-
lithium, LDA or NaH–DMSO as base were disappointing
despite the successful use of these reagents to effect a similar
conversion on a simpler keto ester which lacked a butenyl side
chain at C-5.11 Use of methoxymethyldiphenylphosphine oxide
was also unsuccessful.
Due to the inaccessibility of dialdehyde 5 from methyl vinyl
ether 6, it was decided to alter the synthesis of 6 in light of our
observation that the Wittig reaction of a keto ester analogous
to 10 which lacked the butenyl group at C-5, proceeded in much
higher yield using methyltriphenylphosphonium bromide
rather than methoxymethyltriphenylphosphonium chloride. It
was therefore envisaged that dialdehyde 5 could also be syn-
thesised by the double oxidation of diol 11 which in turn could
be synthesised by effecting a double hydroboration of diene 7.
Treatment of keto ester 10 with methyltriphenylphosphonium
bromide (4 equiv.) using butyllithium as base afforded the
desired diene 7 in 85% yield after heating the reaction mixture
under reflux for 24 h. With diene 7 in hand, attention then
turned to its conversion to diol 11.
Treatment of diene 7 with excess dicyclohexylborane20 only
effected hydroboration of the less hindered olefin in the butenyl
side chain as evidenced by the disappearance of only the res-
1
onances due to the butenyl vinylic protons in the H NMR
spectrum of the crude product. Use of a large excess of borane–
dimethyl sulfide for 24 h similarly did not result in hydrobor-
ation of the more hindered olefin at C-9 and neither did the use
of borane generated in situ from sodium borohydride and
boron trifluoride–diethyl ether and 9-borabicyclo[3.3.1]nonane.
The unsuccessful attempts to prepare dialdehyde 5 from
diene 7 meant that efforts to synthesize the B ring of ABE
tricyclic methyllycaconitine analogues derived from diol 4 using
a pinacol coupling were abandoned. It was therefore decided to
explore alternative avenues to produce tricyclic ABE analogues
of methyllycaconitine.
In an alternative approach for the synthesis of ABE tricyclic
analogues of methylycaconitine 1 it was envisaged that append-
age of a B ring to the AE bicyclic system could be achieved by
intramolecular ring-closure of a suitably appended nucleophile
at C-5 of the azabicyclic system onto the carbonyl group at C-9.
The nucleophile could be generated at this position by forming
the enolate of methyl ketone 12 which in turn can be formed by
Wacker oxidation of alkene 10 (Scheme 3).
Alkene 10 was treated with palladium() chloride (0.2 equiv-
alents) and copper() chloride (1.2 equivalents) and the mixture
stirred overnight whilst bubbling oxygen through the reaction
vessel. After purification of the reaction mixture the desired
product 12 was isolated in 39% yield after purification by flash
chromatography. Use of DMF as solvent maximised the form-
ation of methyl ketone 12 and minimised the competing double
isomerization reaction.21 Copper() chloride was also used
rather than copper() chloride in order to reduce competing
chlorination of the carbonyl group22 and to increase the rate of
the reaction.23
Scheme 3 Reagents, conditions and yields: (i) PdCl2, CuCl, O2, 8 : 1
DMF–H2O, room temp., 24 h (39%) (ii) KOH (4.0 equiv.), EtOH, room
temp., 2 h (96%) (iii) NaBH4, THF, H2O (81%) (iv) NaH, THF, 1 h
then MeI, 20 h (86%) (v) LiAlH4, THF, 0 ЊC, 30 min (86%) (vi)
N-(trifluoroacetyl)anthranilic acid, DMAP, DCC, MeCN, 40 ЊC, 24 h
then NaBH4, EtOH, room temp., 2 h (77%) (vii) 2-methylsuccinic
anhydride, 125 ЊC, 36 h (50%).
azanide or lithium hexamethyldisilazanide only returned start-
ing material as did use of potassium tert-butoxide in THF and
the amino acids phenylalanine and proline. Finally success was
realised when ketone 12 was treated with ethanolic potassium
hydroxide24 for 2 h affording the desired enone 13 in 96% yield
after work up and purification by flash chromatography.
The high resolution mass spectrum recorded for enone 13
exhibited a molecular ion at m/z 291.1827, corresponding to the
molecular formula C17H25NO3 and consistent with loss of water
during the intramolecular aldol condensation of methyl ketone
12. The 1H NMR spectrum exhibited a vinylic proton at δH 5.55
and the infrared spectrum exhibited two carbonyl absorbances
due to the ester and α,β unsaturated ketone at 1727 cmϪ1 and
1676 cmϪ1, respectively. The 13C NMR spectrum showed the
lack of resonances due to C-4Ј at δC 29.7 and C-9 at δC 212.9 in
methyl ketone 12. A new protonated vinylic carbon at δC 120.3
was assigned to C-5 and a quaternary vinylic carbon at δC 167.7
was assigned to C-6.
With the tricyclic framework in place it was then required to
convert the ester in 13 into an alcohol in preparation for
attachment of the N-(methylsuccinimido)anthranilate ester
sidechain. Direct reduction of ester 13 with lithium aluminium
hydride would also introduce a secondary alcohol at C-4. Thus,
in order to prevent complication of the subsequent esterifi-
cation of the C-7 alcohol it was decided to convert the C-4
ketone into a methoxy group, before reduction of the ester. The
With a reliable synthesis of methyl ketone 12 in hand, atten-
tion turned to the use of an intramolecular aldol cyclisation to
convert 12 into enone 13. Treatment of methyl ketone 12 with
potassium hexamethyldisilazanide, sodium hexamethyldisil-
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J. Chem. Soc., Perkin Trans. 1, 2002, 924–931

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ketone at C-4 was therefore selectively reduced with sodium
borohydride to give alcohol 14 which then underwent methyl-
ation to give methyl ether 15. Finally reduction of the ethyl
ester gave the desired primary alcohol 16.
acid using DCC as a coupling agent and attributed this to
complications arising from the presence of nucleophilic imide
carbonyl groups which can react with the activated acid leading
to the formation of 1,3-oxazines.
The initial selective reduction of ketone 13 proceeded readily
in 81% yield using sodium borohydride in THF affording
alcohols 14 as an inseparable 2.3 : 1 mixture of diastereomers
for which the stereochemistry was not assigned. The high
resolution mass spectrum for the mixture of alcohols 14 exhib-
ited a molecular ion at m/z 293.1993, consistent with the
molecular formula C17H27NO3. The infrared spectrum of the
product showed an absorbance at 3354 cmϪ1 indicating a
hydroxy group whilst an absorbance at 1726 cmϪ1 showed that
the ethyl ester was still present. In the 1H NMR spectrum a two
proton multiplet at δH 4.07–4.11 simplified to a single proton
multiplet upon addition of D2O indicating a hydroxy proton
was now present. The vinylic proton, 5-H, which resonated as a
singlet at δH 5.55 in the starting material was observed as two
doublets at δH 5.22 (J5,4 2.2 Hz) and δH 5.31 (J5,4 3.9 Hz) indicat-
ing the presence of two isomeric allylic alcohols. Integration of
the two resonances showed the ratio of isomers to be 2.3 : 1,
with the resonance at δH 5.22 arising from the major isomer and
that at δH 5.31 from the minor isomer.
An alternative two step procedure for attaching the 2-(3-
methyl-2,5-dioxopyrrolin-1-yl)benzoate ester to alcohols 16 was
more fruitful and consisted of conversion of alcohols 16 to
anthranilates 17 followed by reaction with 2-methylsuccinic
acid to afford the 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoates
18. The most common method for conversion of alcohols to
anthranilate esters involves reaction of the alcohol with isatoic
anhydride and catalytic base25 at high temperature, however,
this method only proceeds in low yields when using hindered
alcohols.8,11,14 We therefore developed26 a high yielding and
operationally simple method for the conversion of hindered
alcohols to anthranilate esters which was applied to the con-
version of alcohols 16 to anthranilates 17 in the present work.
Treatment of alcohols 16 with N-(trifluoroacetyl)anthranilic
acid27 and 1,3-dicyclohexylcarbodiimide in acetonitrile using
4-dimethylaminopyridine as acylation catalyst afforded the
N-(trifluoroacetyl)anthranilates which were then on work up
treated directly with sodium borohydride to effect cleavage of
the trifluoroacetyl group affording anthranilates 17 in 77%
yield. Finally fusion of anthranilates 17 with 2-methylsuccinic
anhydride effected conversion to 2-(3-methyl-2,5-dioxopyrrolin-
1-yl)benzoate esters 18 in 50% yield.
In summary the successful synthesis of esters 18 which are
ABE tricyclic analogues of the alkaloid methyllycaconitine
1 has been achieved. The analogues contain the key pharm-
acophore reputed to be responsible for the biological activity
of 1, namely: a homocholine motif formed from a tertiary
N-ethylamine in a 3-azabicyclo[3.3.1]nonane ring system and a
2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoate ester side chain.
The key steps in the synthesis involved the use of a double
Mannich reaction to assemble the 3-azabicyclo[3.3.1]nonane
AE ring system in combination with the use of a Wacker
oxidation–aldol reaction to append a six membered B ring to
the AE framework. Appendage of the 2-(3-methyl-2,5-
dioxopyrrolin-1-yl)benzoate ester was effected by treatment of
alcohols 16 with N-(trifluoroacetyl)anthranilic acid followed by
fusion of the resultant anthranilates with 2-methylsuccinic
anhydride.
The 13C NMR spectrum indicated that the C-4 carbonyl
resonance present in the starting material 13 at δC 198.7 had
disappeared and had been replaced by two new resonances for
C-4 at δC 67.1 for the major isomer and at δC 67.3 for the minor
isomer. The vinylic carbon, C-5, resonated at δC 120.9 for the
major isomer and at δC 119.6 for the minor isomer. All other
carbon resonances were coincidental.
The next step in the synthesis involved the conversion of
alcohols 14 to methyl ethers 15 and was achieved using sodium
hydride and excess methyl iodide in THF. After purification by
flash chromatography methyl ethers 15 were isolated in 86%
1
yield. The H NMR spectrum exhibited two new singlets at δH
3.16 and δH 3.17, which had a combined integration for three
protons, in a ratio of 2.3 : 1. The larger singlet at δH 3.16 was
assigned to the methoxy group of the major isomer whilst the
singlet at δH 3.17 was assigned to the minor isomer. The vinylic
proton, 5-H resonated at δH 5.15 for the major isomer and δH
5.21 for the minor isomer. The 13C NMR spectrum exhibited
distinct resonances for the methoxy group, C-4 and C-5.
Reduction of the ethyl esters 15 to neopentyl alcohols 16 was
achieved using lithium aluminium hydride in THF for 2 hours
at room temperature. After workup, purification by flash
chromatography afforded alcohols 16 as an inseparable 2.3 : 1
mixture of diastereomers in 86% yield. The high resolution
mass spectrum for alcohols 16 exhibited a molecular ion at m/z
265.1974, consistent with the molecular formula C16H26NO2.
The infrared spectrum exhibited a broad absorbance at 3445
cmϪ1 due to the hydroxy group and no carbonyl absorbances,
Experimental
Mps were determined on a Koffler hot-stage apparatus and
are uncorrected. IR spectra were recorded using a Perkin-
Elmer 1600 Fourier Transform IR spectrophotometer as thin
films between sodium chloride plates. Absorption spectra are
expressed in wavenumbers (cmϪ1) with the following abbrevi-
1
ations: s = strong, m = medium, w = weak and br = broad. H
1
confirming reduction of the ester had taken place. The H
NMR spectra were recorded on a Bruker AC 200 (200 MHz) or
a Bruker DRX 400 (400 MHz) spectrometer at ambient tem-
perature. All J-values are given in Hz. Chemical shifts are
expressed in parts per million downfield shift from tetramethyl-
silane as an internal standard, and reported as position (δH),
relative integral, multiplicity (s = singlet, br s = broad singlet,
d = doublet, dd = double doublet, ddd = double double doublet,
t = triplet, q = quartet, m = multiplet) and assignment. 13C
NMR spectra were recorded on a Bruker AC 200 (50.3 MHz)
or a Bruker DRX 400 (100.5 MHz) spectrometer at ambient
temperature with complete proton decoupling. Chemical shifts
are expressed in parts per million downfield shift from tetra-
methylsilane as an internal standard and reported as position
(δC), multiplicity (aided by DEPT 135, DEPT 90, COSY and
HETCOR experiments) and assignment. When NMR data are
reported for isomeric mixtures, resonances for the minor isomer
are denoted by an asterisk (*). Low resolution mass spectra
were recorded on a VG70-250S, a VG70-SD or a AEI model
MS902 double focusing magnetic sector mass spectrometer
NMR spectrum showed the absence of resonances from the
ethyl ester, whilst two doublets at δH 3.37 (Jgem 11.1 Hz) and
δH 3.44 (Jgem 11.1 Hz) were assigned to the C-7 hydroxymethyl
protons. The 13C NMR spectrum showed the absence of reson-
ances due to the ethyl ester and a new methylene resonance at δC
74.4 was assigned to the C-7 hydroxymethyl group. The spec-
trum exhibited individual resonances, for both diastereomers,
for the methoxy group, C-4, C-5 and C-6 whilst all the other
carbons were coincidental.
With the successful synthesis of tricyclic ABE analogues 16
in hand, it next remained to append the key N-(methylsuccin-
imido)anthranilate ester group. Addition of the 2-(3-methyl-
2,5-dioxopyrrolin-1-yl)benzoate ester to alcohols 16 in a single
synthetic step via esterification using 2-(3-methyl-2,5-dioxo-
pyrrolin-1-yl)benzoic acid using methods reported by Kraus
and Dneprovskaia13 were unsuccessful. Whiting et al.14 have
also reported the inability to effect direct esterification of
benzyl alcohol with 2-(3-methyl-2,5-dioxopyrrolin-1-yl)benzoic
J. Chem. Soc., Perkin Trans. 1, 2002, 924–931
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operating with an ionisation potential of 70 eV. High resolution
mass spectra were recorded at nominal resolution of 5000 to
10000 as appropriate. Major fragments are given as percentages
relative to the base peak and assigned where possible. Ionis-
ation methods employed were either electron impact or chem-
ical ionisation with ammonia or methane as reagent gas (CI).
Low resolution chemical ionisation mass spectra were also
recorded on a Hewlett Packard 5989A mass spectrometer using
ammonia as reagent gas with the sample dissolved in methanol.
Elemental analyses were carried out by the Microanalytical
Unit at the Research School of Chemistry, Australian National
University, Canberra. Flash chromatography was performed
using Merck Kieselgel 60 (230–400 mesh) with the indicated
solvents. Thin layer chromatography (tlc) was performed using
0.2 mm thick precoated silica gel plates (Merck Kieselgel 60 F254
or Riedel-de Haen Kieselgel S F254). Compounds were visual-
ised by ultraviolet fluorescence or by staining with iodine or
vanillin in methanolic sulfuric acid.
C-1), 61.7 (CH2, OCH2CH3), 62.5 (CH2, C-4), 65.4 (CH2, C-2),
114.9 (CH , C-4Ј), 139.6 (CH, C-3Ј), 172.1 (quat., OC᎐O),
᎐
2
213.7 (quat., C-9); m/z (EI) 293 (Mϩ, 4), 278 (M Ϫ CH3, 5), 252
(100), 238 (M Ϫ C4H7, 6). Found Mϩ, 293.1979. C17H27NO3
requires Mϩ, 293.1991.
Ethyl (1S*,5S*)-5-(but-3Ј-enyl)-3-ethyl-9-methylidene-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate 7
n-BuLi (3.0 mL, 5.13 mmol, 1.7 M solution in hexane) was
added dropwise to a suspension of methyltriphenylphospho-
nium bromide (2.44 g, 6.83 mmol) in dry THF (40 mL) at Ϫ78
ЊC. The reaction mixture was stirred at 0 ЊC for 10 min then
cooled to Ϫ78 ЊC followed by the dropwise addition of a solu-
tion of ethyl (1R*,5S*)-5-(but-3Ј-enyl)-3-ethyl-9-oxo-3-
azabicyclo[3.3.1]nonane-1-carboxylate 10 (500 mg, 1.70 mmol)
in dry THF (10 mL). The reaction mixture was allowed to
warm to room temperature then heated under reflux for 24 h.
The reaction was quenched with distilled water (5 mL) and the
solvent removed at reduced pressure. The residue was dissolved
in dry ether (40 mL) and extracted with 2 M hydrochloric acid
(3 × 80 mL). The aqueous extract was made basic with 10%
sodium hydroxide solution then extracted with ether (3 ×
100 mL) and dried over anhydrous sodium sulfate. The solvent
was removed at reduced pressure and the resultant dark yellow
oil purified by flash chromatography (19 : 1 hexane–ethyl acet-
ate) to afford the title compound 7 (420 mg, 85%) as a pale
yellow oil. νmax(NaCl)/cmϪ1 1727 (C᎐O, ester), 1640 (C᎐C); δ
Ethyl 3-(but-3Ј-enyl)-2-oxocyclohexane-1-carboxylate 9
A solution of ethyl 2-oxocyclohexane-1-carboxylate 8 (5.58 g,
32.8 mmol) in dry THF (10 mL) was added dropwise to a
suspension of sodium hydride (1.56 g, 65.0 mmol) in dry THF
(100 mL) at 0 ЊC. n-BuLi (21.0 mL, 52.5 mmol, 2.5 M solution
in hexane) was added dropwise to the reaction mixture which
was stirred for 25 min followed by the addition of a solution
of 4-bromobut-1-ene (4.43 g, 32.8 mmol) in dry THF (5 mL).
Stirring was continued at 0 ЊC for 2 h then at room temperature
for 20 h. The reaction mixture was quenched with distilled
water (20 mL) and the solvent removed at reduced pressure to
afford an orange oil. Saturated ammonium chloride solution
(150 mL) was added to the resulting crude oil and the organic
material extracted with ethyl acetate (3 × 100 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate and the solvent was removed at reduced pressure to
afford a dark orange oil. Purification by flash chromatography
(19 : 1 hexane–ethyl acetate) afforded the title compound 9
(6.10 g, 83%) as a yellow oil for which the 1H NMR data were in
agreement with the literature.17
᎐
᎐
H
(400 MHz, CDCl3) 1.08 (3H, t, J 7.1, NCH2CH3), 1.32 (3H, t,
J 7.1, OCH2CH3), 1.40–1.53 (5H, m, 7B-H, 6-CH2 and 8B-H),
1.88–1.98 (3H, m, 1Ј-CH2 and 2Ј-CH2), 2.07–2.26 (2H, m, 4B-H
and 8A-H), 2.31 (2H, q, J 7.1, NCH2CH3) 2.59 (1H, dd,
J2B,4B 2.1, Jgem 10.7, 2B-H), 2.85–2.91 (1H, m, 7A-H), 2.93 (1H,
d, Jgem 11.2, 4A-H), 3.05 (1H, d, Jgem 10.7, 2A-H), 4.22 (2H, q,
J 7.1, OCH2CH3), 4.61 (1H, br s, 10A-H), 4.75 (1H, br s,
10B-H), 4.98 (1H, dd, J4ЈB,3Ј 10.1, Jgem 1.7, 4ЈB-H), 5.06 (1H, dd,
J4ЈA,3Ј 17.1, Jgem 1.7, 4ЈA-H), 5.80–5.90 (1H, m, 3Ј-H); δC
(100 MHz, CDCl3) 13.2 (CH3, NCH2CH3), 14.9 (CH3,
OCH2CH3), 21.7 (CH2, C-7), 28.4 (CH2, C-1Ј), 36.7 (CH2, C-6),
38.4 (CH2, C-8), 38.7 (CH2, C-2Ј), 40.7 (quat., C-5), 52.6 (quat.,
C-1), 52.8 (CH2, NCH2CH3), 61.1 (CH2, OCH2CH3), 62.9
(CH2, C-4), 65.3 (CH2, C-2), 103.7 (CH2, C-10), 114.8 (CH2,
C-4Ј), 140.0 (CH, C-3Ј), 155.4 (quat., C-9) and 175.5 (quat.,
OC᎐O); m/z (EI) 291 (Mϩ, 5), 276 (M Ϫ CH , 9), 262 (M Ϫ
Ethyl (1R*,5S*)-5-(but-3Ј-enyl)-3-ethyl-9-oxo-3-azabicyclo-
[3.3.1]nonane-1-carboxylate 10
᎐
3
A mixture of ethyl 3-(but-3Ј-enyl)-2-oxocyclohexane-1-carb-
oxylate 9 (1.01 g, 4.50 mmol), ethylamine (674 mg, 4.48 mmol,
30% aq. v/v) and formaldehyde (750 mg, 8.99 mmol, 36% aq.
v/v) in ethanol (60 mL) was heated under reflux for 24 h. After
removal of the solvent at reduced pressure, the dark yellow oil
was dissolved in ether (70 mL) and extracted with 2 M hydro-
chloric acid (3 × 80 mL). The aqueous extract was made basic
with 10% sodium hydroxide solution (250 mL) whilst cooling
with ice then extracted with ether (3 × 150 mL) and dried over
anhydrous sodium sulfate. The solvent was removed at reduced
pressure and the resultant yellow oil purified by flash chrom-
atography (9 : 1 hexane–ethyl acetate) to afford the title com-
pound 10 (546 mg, 41%) as a pale yellow oil (Found: C, 69.4; H,
9.2; N, 4.8. C17H27NO3 requires C, 69.6; H, 9.3; N, 4.8%); νmax
(NaCl)/cmϪ1 1736 (C᎐O, ester) and 1718 (C᎐O, ketone), 1640
C2H5, 10), 218 (M Ϫ C2H5CO2, 19) and 58 (100). Found Mϩ,
291.2217. C18H29NO2 requires Mϩ, 291.2198.
Ethyl (1R*,5S*)-3-ethyl-9-oxo-5-(3Ј-oxobutyl)-3-azabicyclo-
[3.3.1]nonane-1-carboxylate 12
A mixture of copper() chloride (445 mg, 4.50 mmol) and pal-
ladium() chloride (133 mg, 0.750 mmol) in DMF (10 mL) and
water (2 mL) was stirred vigorously until the initially brownish
solution became green (approximately 2 h). A solution of ethyl
(1R*,5S*)-5-(but-3Ј-enyl)-3-ethyl-9-oxo-3-azabicyclo[3.3.1]non-
ane-1-carboxylate 10 (1.10 g, 3.75 mmol) in DMF (5 mL) was
then added and oxygen was bubbled through the mixture with
stirring for 18 h. After this time water (100 mL) was added and
the mixture extracted with ethyl acetate (5 × 100 mL). The
combined organic extracts were washed with brine (3 × 100
mL) then dried (MgSO4) and the solvent removed in vacuo to
leave the crude product. Purification by flash chromatography
(4 : 1 hexane–ethyl acetate) afforded the title compound 12 (449
᎐
᎐
(C᎐C); δ (400 MHz, CDCl3) 1.09 (3H, t, J 7.2, NCH2CH3),
᎐
H
1.28 (3H, t, J 7.2, OCH2CH3), 1.41–2.22 (6H, m, 6-CH2, 7B-H,
8B-H, 1Ј-CH2), 2.26–2.29 (1H, m, 2ЈB-H), 2.39 (2H, q, J 7.2,
NCH2CH3), 2.48–2.56 (2H, m, 8A-H, 2ЈA-H), 2.55 (1H, dd,
J4B,2B 1.7, Jgem 11.0, 4B-H), 2.86–2.98 (2H, m, 2B-H, 7A-H),
3.05 (1H, dd, J4A,2A 2.2, Jgem 11.0, 4A-H), 3.18 (1H, dd, J2A,4A
2.2, Jgem 11.3, 2A-H), 4.20 (2H, q, J 7.2, OCH2CH3), 4.92 (1H,
dd, Jgem 1.4, J4ЈB,3Ј 10.1, 4ЈB-H), 5.01 (1H, dd, Jgem 1.4, J4ЈA,3Ј 17.1,
4ЈA-H), 5.74–5.85 (1H, m, 3Ј-H); δC (100 MHz, CDCl3) 13.3
(CH3, NCH2CH3), 14.8 (CH3, OCH2CH3), 21.2 (CH2, C-7),
28.4 (CH2, C-1Ј), 34.7 (CH2, C-6), 37.7 (CH2, C-8), 39.8 (CH2,
C-2Ј), 49.8 (quat., C-5), 51.2 (CH2, NCH2CH3), 59.7 (quat.,
mg, 39%) as an orange oil. νmax(NaCl)/cmϪ1 1732 (C᎐O, ester)
᎐
and 1715 (C᎐O, ketones); δ (200 MHz, CDCl3) 1.04 (3H, t,
᎐
H
J 7.1, NCH2CH3), 1.23 (3H, t, J 7.1, OCH2CH3), 1.37–1.82
(5H, m, 1Ј-CH2, 6-CH2 and 7B-H), 1.94–2.06 (1H, m, 8B-H),
2.09 (3H, s, COCH3), 2.12–2.27 (2H, m, 2Ј-CH2), 2.35 (2H,
q, J 7.1, NCH2CH3), 2.40–2.55 (2H, m, 4B-H and 8A-H),
2.75–2.90 (2H, m, 2B-H and 7A-H), 2.94 (1H, dd, J4A,2A 2.1,
Jgem, 11.3, 4A-H), 3.21 (1H, dd, J2A,4A 2.1, Jgem, 11.3, 2A-H) and
928
J. Chem. Soc., Perkin Trans. 1, 2002, 924–931

View Article Online
4.15 (2H, q, J 7.1, OCH2CH3); δC (50 MHz, CDCl3) 12.5
(CH3, NCH2CH3), 14.0 (CH3, OCH2CH3), 20.2 (CH2, C-7),
28.4 (CH2, C-1Ј), 29.7 (CH3, C-4Ј), 36.7 (CH2, C-6), 38.3 (CH2,
C-8), 39.4 (CH2, C-2Ј), 48.7 (quat., C-5), 51.0 (CH2,
NCH2CH3), 58.8 (quat., C-1), 61.0 (CH2, OCH2CH3), 61.6
(CH2, C-2), 32.4 (CH2, C-11), 34.2 (CH2, C-3), 36.2 (quat.,
C-1), 38.8 (CH2, C-13), 38.9 (quat., C-7), 51.8 (CH2,
NCH2CH3), 60.5 (CH2, OCH2CH3), 61.9 (CH2, C-10), 66.9
(CH2, C-8), 67.1 (CH, C-4), 67.3* (CH, C-4), 119.6* (CH, C-5),
120.9 (CH, C-5), 145.2 (quat., C-6) and 179.6 (quat., OC᎐O);
᎐
(CH , C-4), 64.7 (CH , C-2), 171.1 (quat., OC᎐O), 208.5
m/z (EI) 293 (Mϩ, 40%), 278 (M Ϫ CH3, 78), 264 (M Ϫ
CH2CH3, 14), 220 (M Ϫ COOC2H5, 42) and 42 (100). Found
Mϩ, 293.1993. C17H27NO3 requires Mϩ, 293.1991.
᎐
2
2
(quat., C-3Ј) and 212.9 (quat., C-9); m/z (EI) 309 (Mϩ, 23%),
266 (M Ϫ CH3CO, 21), 252 (M Ϫ C3H5O, 98), 238 (M Ϫ
C4H7O, 13) and 43 (CH3CO, 100). Found Mϩ, 309.1958.
C17H27NO4 requires Mϩ, 309.1940.
Ethyl (1R*,7S*)-9-ethyl-4-methoxy-9-azatricyclo[5.3.3.01,6]-
tridec-5-ene-7-carboxylate 15
Ethyl (1R*,7S*)-9-ethyl-4-oxo-9-azatricyclo[5.3.3.01,6]tridec-5-
To a suspension of sodium hydride (219 mg, 60% in oil, 5.48
mmol) in dry THF (20 mL) at 0 ЊC was added a solution
of ethyl (1R*,7S*)-9-ethyl-4-hydroxy-9-azatricyclo[5.3.3.01,6]tri-
dec-5-ene-7-carboxylate 14 (535 mg, 1.82 mmol) in dry THF
(5 mL). The mixture was then stirred for 1 h after which time
iodomethane (776 mg, 0.34 mL, 5.47 mmol) was added and the
mixture stirred at room temperature for 20 h. The reaction was
quenched by the careful addition of sat. ammonium chloride
solution (20 mL). The volatile solvents were removed in vacuo
and the remaining aqueous mixture was diluted with water
(50 mL) and extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were washed with brine (50 mL) then
dried (MgSO4) and concentrated in vacuo to give the crude
product which was purified by flash chromatography (7 : 3
hexane–ethyl acetate) to give the title compound 15 (484 mg,
86%) as a clear oil and as a 2.3 : 1 inseparable mixture of
ene-7-carboxylate 13
To a solution of potassium hydroxide (0.524 g, 9.33 mmol) in
ethanol (25 mL) was added a solution of ethyl (1R*,5S*)-3-
ethyl-9-oxo-5-(3Ј-oxobutyl)-3-azabicyclo[3.3.1]nonane-1-carb-
oxylate 12 (0.723 g, 2.33 mmol) in ethanol (25 mL) and the
mixture stirred for 1.5 h at room temperature. After this time
brine (20 mL) was added and the solution diluted with water
(100 mL). The aqueous solution was extracted with diethyl
ether (3 × 50 mL), the combined organic layers washed with
brine (50 mL) then dried (MgSO4) and concentrated in vacuo to
give the crude product. Further purification by flash chrom-
atography (7 : 3 hexane–ethyl acetate) afforded the title com-
pound 13 (0.657 g, 96%) as a clear oil. νmax(NaCl)/cmϪ1 2924
(C–H), 1727 (C᎐O, ester), 1676 (C᎐C–C᎐O), 1617 (C᎐C), 1457
᎐
᎐
᎐
᎐
and 1251; δH (200 MHz, CDCl3) 0.98 (3H, t, J 7.2, NCH2CH3),
1.18 (3H, t, J 7.1, OCH2CH3), 1.41–1.49 (1H, m, 12B-H),
1.60–1.95 (5H, m, 2-CH2, 11-CH2 and 13B-H), 2.00–2.35 (6H,
m, 3-CH2, 10B-H, 13A-H and NCH2CH3), 2.55 (1H, dd,
J8B,10B 1.9, Jgem, 11.0, 8B-H), 2.81 (1H, dd, J10A,8A 1.1, Jgem, 11.8,
10A-H), 2.82–2.97 (1H, m, 12A-H), 3.00 (1H, dd, J8A,10A 1.1,
Jgem, 11.0, 8A-H), 4.09 (2H, q, J 7.1, OCH2CH3) and 5.55 (1H,
br s, 5-H); δC (50 MHz, CDCl3) 12.2 (CH3, NCH2CH3), 13.9
(CH3, OCH2CH3), 20.3 (CH2, C-12), 32.8 (CH2, C-2), 33.1
(CH2, C-11), 36.5 (CH2, C-3), 37.3 (quat., C-1), 38.1 (CH2,
C-13), 51.3 (CH2, NCH2CH3), 51.8 (quat., C-7), 60.8 (CH2,
OCH2CH3), 61.1 (CH2, C-10), 66.0 (CH2, C-8), 120.3 (CH,
isomers. νmax(NaCl)/cmϪ1 2932 (C–H), 1727 (C᎐O, ester), 1661
᎐
(C᎐C), 1453 and 1252; δ (200 MHz, CDCl ) 0.89 (3H, t, J 7.1,
᎐
H
3
NCH2CH3), 1.12 (3H, t, J 7.0, OCH2CH3), 1.27–1.48 (5H, m,
2-CH2, 11B-H, 12B-H and 13B-H), 1.56–1.88 (4H, m, 3-CH2,
11A-H and 13A-H), 2.09 (2H, q, J 7.1, NCH2CH3), 2.28 (1H, d,
Jgem, 10.5, 10B-H), 2.43 (1H, d, Jgem, 10.8, 8B-H), 2.60 (1H,
d, Jgem, 10.5, 10A-H), 2.63–2.79 (1H, m, 12A-H), 2.84 (1H, d,
Jgem, 10.8, 8A-H), 3.16 (2.1H, s, OCH3), 3.17* (0.9H, s, OCH3),
3.54–3.58 (1H, m, 4-H), 4.01 (2H, q, J 7.0, OCH2CH3), 5.15
(0.7H, br s, 5-H) and 5.21* (0.3H, d, J5,4 3.6, 5-H); δC (50 MHz,
CDCl3) 12.2 (CH3, NCH2CH3), 13.9 (CH3, OCH2CH3), 20.7
(CH2, C-12), 23.9 (CH2, C-2), 32.1 (CH2, C-11), 35.1 (quat.,
C-1), 35.6 (CH2, C-3), 38.7 (CH2, C-13), 39.0 (quat., C-7), 51.6
(CH2, NCH2CH3), 55.2 (CH3, OCH3), 55.6* (CH3, OCH3), 60.0
(CH2, OCH2CH3), 61.8 (CH2, C-10), 66.7 (CH2, C-8), 73.9 and
75.4* (CH, C-4), 117.0* (CH, C-5), 117.9 (CH, C-5), 145.1
C-5), 167.7 (quat., C-6), 172.4 (quat., OC᎐O) and 198.7 (quat.,
᎐
C-4); m/z (EI) 291 (Mϩ, 65%), 276 (M Ϫ CH3, 60), 262 (M Ϫ
CH2CH3, 61), 218 (M Ϫ CO2C2H5, 44) and 58 (100). Found
Mϩ, 291.1827. C17H25NO3 requires Mϩ, 291.1834.
Ethyl (1R*,7S*)-9-ethyl-4-hydroxy-9-azatricyclo[5.3.3.01,6]-
(quat., C-6) and 173.7 (quat., OC᎐O); m/z (EI) 307 (Mϩ, 29%),
᎐
tridec-5-ene-7-carboxylate 14
292 (M Ϫ CH3, 44), 278 (M Ϫ CH2CH3, 22), 276 (M Ϫ OCH3,
34), 234 (M Ϫ COOC2H5, 42) and 29 (CH3CH2, 100). Found
Mϩ, 307.2143. C18H29NO3 requires Mϩ, 307.2147.
To a solution of sodium borohydride (86 mg, 2.27 mmol) in
THF (3 mL) and water (7 mL) was added a solution of ethyl
(1R*,7S*)-9-ethyl-4-oxo-9-azatricyclo[5.3.3.01,6]tridec-5-ene-7-
carboxylate 13 (0.657 g, 2.25 mmol) in THF (4 mL) and the
mixture stirred for 8 h. After this time the reaction was
quenched by the addition of water (20 mL) and the volatiles
were removed in vacuo. The remaining aqueous solution was
extracted with ethyl acetate (3 × 30 mL), the combined organic
layers washed with brine (50 mL) then dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by
flash chromatography (7 : 3 hexane–ethyl acetate) to give the
title compound 14 (0.535 g, 81%) as a clear oil and as a 2.3 : 1
inseparable mixture of isomers. νmax(NaCl)/cmϪ1 3354 (O–H),
(1R*,7S*)-(9-Ethyl-4-methoxy-9-azatricyclo[5.3.3.01,6]tridec-5-
en-7-yl)methanol 16
To a slurry of lithium aluminium hydride (109 mg, 2.87 mmol)
in dry THF (20 mL) at 0 ЊC, was slowly added a solution of
ethyl (1R*,7S*)-9-ethyl-4-methoxy-9-azatricyclo[5.3.3.01,6]tri-
dec-5-ene-7-carboxylate 15 (442 mg, 1.44 mmol) in dry THF
(20 mL) and the mixture stirred under an atmosphere of nitro-
gen for 30 min. The reaction was quenched by the slow addition
of water (30 mL) and the volatiles removed in vacuo. The
remaining aqueous mixture was extracted with ethyl acetate
(3 × 20 mL) and the combined organic layers washed with brine
(40 mL) then dried (Na2SO4) and concentrated in vacuo to
give the crude product. Further purification by flash chrom-
atography (1 : 1 hexane–ethyl acetate) afforded the title com-
pound 16 (329 mg, 86%) as a clear oil and as a 2.3 : 1 inseparable
mixture of isomers. νmax(NaCl)/cmϪ1 3445 (O–H), 2929 (C–H),
2931 (C–H), 1726 (C᎐O, ester), 1661 (C᎐C), 1451 and 1253;
᎐
᎐
δH (200 MHz, CDCl3) 1.02 (3H, t, J 7.2, NCH2CH3), 1.26 (3H,
t, J 7.1, OCH2CH3), 1.38–1.59 (5H, m, 2-CH2, 11B-H, 12B-H
and 13B-H), 1.64–1.96 (4H, m, 3-CH2, 11A-H and 13A-H),
2.13 (1H, dd, J10B,8B 2.0, Jgem, 10.3, 10B-H), 2.24 (2H, q, J 7.2,
NCH2CH3), 2.51 (1H, dd, J8B,10B 2.0, Jgem, 10.8, 8B-H), 2.74
(1H, d, Jgem, 10.3, 10A-H), 2.79–2.92 (1H, m, 12A-H), 2.99 (1H,
d, Jgem, 10.8, 8A-H), 4.07–4.11 (2H, m, 4-H and OH), 4.16 (2H,
q, J 7.1, OCH2CH3), 5.22 (0.7H, d, J5,4 2.2, 5-H) and 5.31*
(0.3H, d, J5,4 3.9, 5-H); δC (50 MHz, CDCl3) 12.4 (CH3,
NCH2CH3), 14.1 (CH3, OCH2CH3), 20.9 (CH2, C-12), 28.3
1654 (C᎐C), 1452 and 1084; δ (200 MHz, CDCl ) 0.92 (3H, t,
᎐
H
3
J 7.1, NCH2CH3), 1.28–1.64 (7H, m, 2-CH2, 11-CH2, 12B-H
and 13-CH2), 1.70–1.82 (3H, m, 3-CH2, 10B-H), 2.11 (2H, q,
J 7.2, NCH2CH3), 2.64 (1H, d, Jgem, 10.4, 8B-H), 2.71–2.82 (2H,
m, 10A-H and 12A-H), 2.89 (1H, d, Jgem, 10.4, 8A-H), 3.11 (1H,
J. Chem. Soc., Perkin Trans. 1, 2002, 924–931
929

View Article Online
brs, OH), 3.22 (2.1H, s, OCH3), 3.24* (0.9H, s, OCH3), 3.37
(1H, d, Jgem 11.1, CHAHBOH), 3.44 (1H, d, Jgem, 11.1, CHA-
HBOH), 3.57–3.70 (1H, m, 4-H), 5.20 (0.7H, d, J5,4 1.5, 5-H)
and 5.28* (0.3H, d, J5,4 3.8, 5-H); δC (50 MHz, CDCl3) 12.5
(CH3, NCH2CH3), 20.7 (CH2, C-12), 23.9 (CH2, C-2), 31.5
(CH2, C-11), 35.6 (quat., C-1), 36.2 (CH2, C-3), 39.0 (quat.,
C-7), 41.3 (CH2, C-13), 51.8 (CH2, NCH2CH3), 55.3 (CH3,
OCH3), 55.4* (CH3, OCH3), 62.1 (CH2, C-10), 67.9 (CH2, C-8),
74.4 (CH2, OCH2), 75.9 (CH, C-4), 76.3* (CH, C-4), 114.5*
(CH, C-5), 115.7 (CH, C-5), 147.8 (quat., C-6) and 149.3*
(quat., C-6); m/z (EI) 265 (Mϩ, 1%), 250 (M Ϫ CH3, 9), 234
(M Ϫ OCH3, 10) and 72 (100). Found Mϩ, 265.1974.
C16H26NO2 requires Mϩ, 265.1964.
bicarbonate solution (30 mL) and brine (30 mL) then dried
(MgSO4) and concentrated in vacuo. The crude product was
purified by flash chromatography using 3 : 2 hexane–ethyl acet-
ate as eluent to afford the title compound 18 (45 mg, 50%) as a
yellow oil and as a mixture of isomers. νmax(NaCl)/cmϪ1 2931
(C–H), 1781 (N–C᎐O), 1716 (C᎐O), 1602, 1493, 1454, 1391,
᎐
᎐
1259 and 1186; δH (200 MHz, CDCl3) 1.03 (3H, t, J 7.1,
NCH2CH3), 1.20–1.35 (2H, m, 11ЉB-H and 12ЉB-H), 1.35–1.74
(9H, m, 3Ј-CH3, 2Љ-CH2, 3Љ-CH2, 11ЉA-H and 13Љ-H), 1.79 (1H,
d, Jgem 11.2, 10ЉB-H), 1.96 (2H, q, J 7.2, NCH2CH3), 2.13–2.29
(2H, m, 10ЉA-H and 13ЉA-H), 2.45–2.68 (1H, m, 3Ј-H), 2.79
(1H, d, Jgem 10.3, 8ЉB-H), 2.83–3.09 (4H, br m, 4Ј-CH2, 8ЉA-H
and 12ЉA-H), 3.33 (2.1H, s, OCH3), 3.36* (0.9H, s, OCH3),
3.68–3.81 (1H, m, 4Љ-H), 4.12 (2H, br s, OCH2), 5.36 (0.7H, d,
J5Љ,4Љ 2.0, 5Љ-H), 5.43* (0.3H, d, J5Љ,4Љ 3.9, 5Љ-H), 7.24 (1H, dd,
J 1.1, 7.7, 3-H), 7.51 (1H, td, J 7.8, 1.4, 5-H), 7.65 (1H, td, J 7.7,
1.7, 4-H) and 8.08 (1H, dd, J 1.6, 7.8, 6-H); δC (50 MHz,
CDCl3) 12.5 (CH3, NCH2CH3), 16.3 (CH3, 3Ј-CH3), 20.9 (CH2,
C-12Љ), 24.3 (CH2, C-2Љ), 32.2 (CH2, C-11Љ), 35.2 (CH, C-3Ј),
36.2 (quat., C-1Љ), 36.5 (quat., C-3Љ), 36.9 (CH2, C-4Ј), 39.1
(CH2, C-13Љ), 40.7 (quat., C-7Љ), 52.0 (CH2, NCH2CH3), 55.7
(CH3, OCH3), 55.9* (CH3, OCH3), 62.6 (CH2, C-10Љ), 67.2
(CH2, C-8Љ), 70.5 (CH2, OCH2), 74.3* (CH, C-4Љ), 75.9 (CH,
C-4Љ), 115.4* (CH, C-5Љ), 116.5 (CH, C-5Љ), 127.2 (quat., C-1),
129.3 (CH, C-5), 129.8 (CH, C-3), 131.4 (CH, C-6), 132.8
(quat., C-2), 133.3 (CH, C-4), 147.0 (quat., C-6Љ), 148.5* (quat.,
(1ЈR*,7ЈS*)-(9-Ethyl-4-methoxy-9-azatricyclo[5.3.3.01,6]tridec-
5-en-7-yl)methyl 2-aminobenzoate 17
To a mixture of alcohol 16 (70 mg, 0.264 mmol), N-
(trifluoroacetyl)anthranilic acid26,27 (246 mg, 1.06 mmol) and
4-(dimethylamino)pyridine (32 mg, 0.262 mmol) in acetonitrile
(5 mL) was added 1,3-dicyclohexylcarbodiimide (217 mg, 1.05
mmol) and the mixture stirred, under an atmosphere of nitro-
gen, at 40 ЊC for 24 h. After this time the mixture was cooled,
filtered and the filtrate evaporated to dryness. The crude mix-
ture was then dissolved in dichloromethane (20 mL), washed
with aq. sodium bicarbonate (20 mL) and brine (20 mL) then
dried (MgSO4) and concentrated in vacuo to leave the crude N-
(trifluoroacetyl)anthranilate ester. This residue was suspended
in absolute ethanol (10 mL), sodium borohydride (50 mg, 1.32
mmol) added, and the mixture stirred for 2 h. The reaction was
quenched by the addition of water and the volatile solvent
removed in vacuo. The remaining aqueous solution was
extracted with ethyl acetate (2 × 30 mL) and the combined
organic layers washed with brine (50 mL) then dried (MgSO4)
and concentrated in vacuo to leave the crude product, which
was purified by flash chromatography using 7 : 3 hexane–ethyl
acetate as eluent to afford the title compound 17 (78 mg, 77%)
as a yellow oil and as a 2.3 : 1 inseparable mixture of isomers.
C-6Љ), 164.2 (quat., OC᎐O), 175.8 (quat., C-5Ј) and 179.9
᎐
(quat., C-2Ј); m/z (EI) 480 (Mϩ, 26%), 449 (M Ϫ OCH3, 26), 264
(M Ϫ C12H10O3N, 67), 248 (M Ϫ C12H10O4N, 61) and 72 (100).
Found Mϩ, 480.2619. C28H36N2O5 requires Mϩ, 480.2624.
References
1 R. H. Manske, Can. J. Res., Sect B, 1938, 16, 57.
2 S. W. Pelletier, N. V. Mody, B. S. Joshi and L. C. Schramm, in
Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier,
J. Wiley and Sons, New York, 1984, vol. 2, p. 205.
3 S. W. Pelletier and B. S. Joshi, in Alkaloids: Chemical and Biological
Perspectives, ed. S. W. Pelletier, Springer-Verlag, New York, 1991,
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νmax(NaCl)/cmϪ1 3474 and 3370 (N–H), 2929 (C–H), 1689 (C᎐
᎐
O), 1617, 1589, 1453, 1244 and 1099; δH (200 MHz, CDCl3)
1.04 (3H, t, J 7.2, NCH2CH3), 1.28–1.69 (8H, m, 2Ј-CH2, 3Ј-
CH2, 11Ј-CH2, 12ЈB-H and 13ЈB-H), 1.81 (1H, d, Jgem 11.2,
10ЈB-H), 2.00 (2H, q, J 7.2, NCH2CH3), 2.10–2.28 (2H, m,
10ЈA-H and 13ЈA-H), 2.80 (1H, d, Jgem, 10.4, 8ЈB-H), 2.84–3.04
(1H, m, 12ЈA-H), 3.06 (1H, d, Jgem, 10.4, 8ЈA-H), 3.34 (2.1H, s,
OCH3), 3.37* (0.9H, s, OCH3), 3.70–3.85 (1H, m, 4Ј-H), 4.21
(2H, br s, OCH2), 5.42 (0.7H, d, J5Ј,4Ј 1.9, 5Ј-H), 5.50* (0.3H, d,
J5Ј,4Ј 3.9, 5Ј-H), 5.73 (2H, brs, NH2), 6.60–6.68 (2H, m, 3-H
and 5-H), 7.26 (1H, td, J 7.4, 1.9, 4-H) and 7.84 (1H, dd, J 1.4,
8.1, 6-H); δC (50 MHz, CDCl3) 12.5 (CH3, NCH2CH3), 21.0
(CH2, C-12Ј), 24.3 (CH2, C-2Ј), 32.3 (CH2, C-11Ј), 36.4 (CH2,
C-3Ј), 36.5 (quat., C-1Ј), 39.2 (CH2, C-13Ј), 40.7 (quat., C-7Ј),
52.0 (CH2, NCH2CH3), 55.7 (CH3, OCH3), 55.8* (CH3,
OCH3), 62.8 (CH2, C-10Ј), 67.3 (CH2, C-8Ј), 67.7 (CH2,
OCH2), 74.4* (CH, C-4Ј), 76.0 (CH, C-4Ј), 110.2 (quat., C-1),
115.3* (CH, C-5Ј), 116.2 (CH, C-5Ј), 116.4 (CH, C-3), 116.6
(CH, C-5), 131.1 (CH, C-6), 134.0 (CH, C-4), 149.3 (quat., C-
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6Ј), 150.5 (quat., C-2) and 166.9 (quat., OC᎐O); m/z (EI) 384
᎐
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(Mϩ, 37%), 369 (M Ϫ CH3, 29), 353 (M Ϫ OCH3, 27), 264 (M
Ϫ NH2C6H4CO, 56), 248 (M Ϫ NH2C6H4CO2, 57), 120
(C7H6NO, 69) and 72 (100). Found Mϩ, 384.2419. C23H32N2O3
requires Mϩ, 384.2413.
(1ЉR*,7ЉS*,3ЈR*)- and (1ЉR*,7ЉS*,3ЈS*)-(9-Ethyl-4-methoxy-9-
aza-tricyclo[5.3.3.01,6]tridec-5-en-7-yl)methyl 2-(3-methyl-2,5-
dioxopyrrolidin-1-yl)benzoate 18
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125 ЊC for 36 h. After this time the crude mixture was dissolved
in warm ethyl acetate (10 mL), washed with sat. sodium
930
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