Synthesis of simple analogues of methyllycaconitine - An efficient method for the preparation of the N-substituted anthranilate pharmacophore

Article abstract of DOI:10.1016/j.tet.2004.05.024

The synthesis of several A and AE ring analogues of the alkaloid methyllycaconitine is reported. The key 2-(2″-methylsuccinimido)benzoate ester pharmacophore is introduced using an efficient two step procedure. Esterification of the alcohol precursors with N-(trifluoroacetyl)anthranilic acid under Steglich conditions followed by sodium borohydride mediated cleavage of the trifluoroacetyl group affords the anthranilate esters. Subsequent fusion with methylsuccinic anhydride affords the N-substituted anthranilate derivatives containing the key pharmacophore present in a range of commonly occurring Delphinium and Aconitum alkaloids.

Full text of DOI:10.1016/j.tet.2004.05.024

Tetrahedron 60 (2004) 5953–5963
Synthesis of simple analogues of methyllycaconitine—an efficient
method for the preparation of the N-substituted
anthranilate pharmacophore
a
David Barker,a Margaret A. Brimbleb and Malcolm D. McLeod
,
*
aSchool of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
bDepartment of Chemistry, University of Auckland, Private Bag 92019, 23 Symonds St., Auckland, New Zealand
Received 16 January 2004; revised 19 April 2004; accepted 13 May 2004
Available online 8 June 2004
Abstract—The synthesis of several A and AE ring analogues of the alkaloid methyllycaconitine is reported. The key 2-(200-
methylsuccinimido)benzoate ester pharmacophore is introduced using an efficient two step procedure. Esterification of the alcohol precursors
with N-(trifluoroacetyl)anthranilic acid under Steglich conditions followed by sodium borohydride mediated cleavage of the trifluoroacetyl
group affords the anthranilate esters. Subsequent fusion with methylsuccinic anhydride affords the N-substituted anthranilate derivatives
containing the key pharmacophore present in a range of commonly occurring Delphinium and Aconitum alkaloids.
q 2004 Elsevier Ltd. All rights reserved.
Nicotinic acetylcholine receptors (nAchRs) are a family of
ligand gated ion channels that are widely distributed in the
human brain.1,2 These receptors have numerous receptor
subtypes composed of combinations of a2-7, a9-10 and
b2-4 subunits.3 nAchRs are involved in a number of
physiological and behavioural conditions hence there is a
pressing need for subtype selective agonists and antagonists
to elucidate the biological roles of these receptors and to
provide candidates for drug discovery. The a7 nAChR
subtype is amongst the most prevalent in the brain and has
been implicated as playing a key role in conditions such as
schizophrenia, Alzheimer’s disease and epilepsy.4 Methyl-
lycaconitine (MLA) 15 is one of only a few compounds
(including the peptide toxins a-bungarotoxin6 and
a-conotoxin ImI7) that binds with high affinity and
selectivity to the a7 nAChR. MLA 1 is therefore a prime
lead compound for development of new therapies targeting
the a7 nAChR. We have therefore embarked on a
programme to provide novel compounds that may help
elucidate the key structural features of nAChR ligands that
give rise to binding affinity, subtype selectivity and agonist/
antagonist activity.
MLA 1 is the major toxic component of Delphinium
brownii8 and is a potent antagonist of the a7 nAChR in
mammalian neuronal membranes. Furthermore, it exhibits
very high selectivity for this subtype over other neuronal
nAChRs rendering it a prime lead for the development of
new therapeutic agents targeting the a7 nAChR. Structure
activity studies on MLA have shown the N-substituted
anthranilate ester moiety is an essential structural feature for
pharmacological activity9 and competitive ligand binding
studies revealed that MLA 1 containing the 2-(20-methyl-
succinimido)benzoate ester sidechain displays ca. 103 times
more potent inhibition that the parent alkaloid lycoctonine
2.10 It has also been proposed that the tertiary amine and
ester sidechain of MLA form an acylated homocholine
pharmacophore at physiological pH that gives rise to the
high affinity nicotinic acetylcholine receptor binding.
A number of approaches to the synthesis of small molecule
analogues of MLA incorporating the putative pharmaco-
phore have been reported, including the synthesis of E,11
AE12 and AEF13 ring systems, some of which display
Keywords: Methyllycaconitine; Anthranilate esters; Nicotinic acetylcholine
receptors; Alkaloids.
*
Corresponding author. Tel.: þ64-9-3737599x88259; fax: þ64-9-
3737422; e-mail address: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.024

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D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
significant biological activity.11,14 Given the demonstrated
importance of the N-substituted anthranilate sidechain to the
pharmacology of MLA analogues, we herein report15 the
full synthetic details for several analogues of MLA prepared
using our recently developed efficient procedure for the
introduction of this key structural unit.
investigations into the introduction of this sidechain by
alternative procedures,13,18 however none of these methods
has offered a general and high yielding solution to the
problem of sidechain introduction.
In connection with our studies towards MLA analogues we
turned our attention to the use of N-(trifluoroacetyl)anthra-
nilic acid 619 and the coupling procedure developed by
Breslow19 as an alternative to the isatoic anhydride
mediated synthesis. Initial attempts to repeat this coupling
procedure on stoichiometric quantities of the alkoxide salt
derived from 1-methyl-3-piperidinemethanol (7, Table 1)
did not result in practical yields of the coupled product.
However, reaction of 7 with 3 equiv. of N-(trifluoroacetyl)-
anthranilic acid 6 under Steglich conditions11 (DCC/
DMAP) followed directly by sodium borohydride mediated
cleavage of the crude amide gave a gratifying 81% yield of
the anthranilate ester. This compares favourably with the
base catalysed reaction of isatoic anhydride, which in our
hands proceeded in 72% yield (Table 1, entry 1).16b This
high yielding and operationally simple anthranilate ester
synthesis prompted us to explore the scope of this coupling
reaction as an alternative approach.
Previous syntheses of Delphinium alkaloids and their
analogues that contain a 2-(20-methylsuccinimido)benzoate
ester sidechain have made use of one of two methods
(Scheme 1). The first method involves a two-step process
using isatoic anhydride 3 to convert the alcohol into an
anthranilate16 then adding methylsuccinic anhydride 4 to
form the desired cyclic imide. The second more convergent
method involves direct addition of the entire 2-(3-methyl-
2,5-dioxopyrrolidin-1-yl)benzoate group to the alcohol in a
single step by esterification of the alcohol with acid 5.
Kraus and Dneprovskaia13b reported the esterification of 2-
(3-methyl-2,5-dioxopyrrolidin-1-yl)benzoic acid 5 by for-
mation of the sodium salt of acid 5 followed by treatment
with oxalyl chloride to generate the acid chloride, however
our attempts to repeat this procedure met with little success.
The same authors also reported that this high yielding
esterification procedure failed to work using more hindered
neopentyl-type alcohols giving mixtures of the desired ester
and undesired isomeric carbamate by-product, and the
procedure failed completely when using tertiary alcohols.
They overcame this problem by effecting an SN2 displace-
ment of the neopentyl mesylate by the sodium salt of acid 5.
In our hands this procedure failed to give significant
quantities of the anthranilate ester of the model compound,
1-methyl-3-piperidinemethanol 7 (Table 1). Bergmeier and
co-workers11a reported that esterification of acid 5 using the
coupling agent, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-
methyluronium tetrafluoroborate (TBTU) was inconsistent
with yields ranging from 6 to 60%.
This two step coupling procedure was studied using a range
of primary, neopentyl, secondary and tertiary alcohols
together with the azabicyclic neopentyl alcohols 8, 9
(Table 1) and diol 10 (Scheme 3). Heating ethyl 2-oxo-
cyclohexane carboxylate with ethylamine and formal-
dehyde, according to the method of Iwai et al.21 afforded
the double Mannich adduct 11 (Scheme 2) that underwent
Wittig reaction with the ylide derived from methyltri-
phenylphosphonium bromide to afford alkene 12 and thence
alcohol 8 upon reduction of the ester with LiAlH4.
Reduction of keto ester 11 afforded a 1:1.25 mixture of
the alcohols 13 and 14 and the major isomer 14 underwent
smooth methylation to methyl ether 15, followed by
reduction of the ester to alcohol 9. Direct reduction of 11
with LiAlH4 afforded diol 10 that was used to probe the
selective esterification of the neopentyl alcohol using this
coupling procedure.
Use of isatoic anhydride 3 as developed by Blagbrough17
has been adopted by others to append the anthranilate ester
group to MLA analogues.13 In general, low yields (typically
40–65%) of the desired anthranilate esters are obtained
which can be attributed to the hindered neopentyl
environment of the C-18 hydroxyl group present in
lycoctonine and many simpler analogues. The low yields
of ester formation by these methods have prompted
The reaction of a range of simple primary alcohols with
N-(trifluoroacetyl)anthranilic acid 6 afforded good yields of
the anthranilate esters in comparison with the isatoic
anhydride mediated synthesis (Table 1, entries 2, 3 and 4).
Scheme 1.

D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
Table 1. Synthesis of anthranilate esters with N-(trifluoroacetyl)anthranilic acid 6
5955
Entry
Alcohol
Product
Yield of ester (%)a
1
81 (72)b,c
7
16
17
2
3
85 (75)b,c
94 (64)b,d
18
19
4
85 (90)b,e
5
75 (40)b,c
8
20
6
78 (65)b,d
9
21
7
8
97 (16)b,c
22
23
24
91
9
39 (77)f
a
d
Yield of anthranilate ester prepared by alternative literature based methods in parentheses.
Prepared by reaction with isatoic anhydride.
Prepared according to Ref. 16b.
See Ref. 17c.
See Ref. 16b.
See Ref. 19.
b
c
e
f

5956
D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
Scheme 2. Reagents and conditions: (a) EtNH2, CH2O, EtOH, reflux, 30 h, 27%; (b) n-BuLi, MePPh3Br, THF, 92%; (c) LiAlH4, THF, room temperature,
10 min, 94%; (d) NaBH4, 1:1 THF/H2O, 0 8C, 30 min, 81%; (e) NaH, MeI, THF, 0 8C, 70%; (f) LiAlH4, THF, room temperature, 2 h, 91%; (g) LiAlH4, THF,
room temperature, 1 h, 54%.
Extension of this procedure to AE bicyclic analogues of
MLA, 8 and 917d (Table 1, entries 5 and 6) containing
neopentyl substituted alcohols, also afforded coupled
product in improved yield.
reaction of bicyclic diol 10 with 1 equiv. of acid 6 favoured
reaction at the primary hydroxyl to give mono-anthranilate
ester 25 in 56%, together with a small quantity of the diester
26 (10%). Reaction of 10 with 2 equiv. of acid 6 gave the
di-ester 26 in a moderate 48% yield.
Secondary alcohols were observed to react readily with 6 to
afford high yields of the anthranilate ester (Table 1, entries 7
and 8) providing the first direct, high yielding synthesis of
anthranilate esters derived from secondary alcohols reported
in the literature.16 Attempts to promote the esterification of
tertiary alcohols however, afforded lower yields of the
coupled product, in line with the synthesis of t-butyl
benzoate ester derivatives initially reported by Steglich.20
The use of di-2-pyridyl thiocarbonate, recommended22 for
the synthesis of esters derived from tertiary alcohols, failed
to give the desired product.
Finally, heating the anthranilate esters with 2 equiv. of
2-methylsuccinic acid at 125 8C according to the procedure
of Blagbrough17c cleanly afforded the succinimide
derivatives in good yield (Table 2). This procedure 0therefore
offers a simple two step synthesis of the 2-(2 -methyl-
succinimido)benzoate ester sidechain present in methyl-
lycaconitine 1 and other Delphinium alkaloids.
In conclusion, we have developed a practical, high
yielding synthesis of anthranilate esters from primary
and secondary alcohols using N-(trifluoroacetyl)anthranilic
acid 6. The reactions proceed under mild conditions
and offer a practical alternative to existing procedures.
The method has wide applicability for the synthesis
of diterpenoid alkaloids such as methyllycaconitine 1
and their analogues and has been readily adopted by us
for the synthesis of more complex tricyclic analogues of
MLA.
The extreme conditions associated with the isatoic
anhydride mediated synthesis of anthranilate esters have
been reported to lead to poor regioselectivity or possibly
transesterification during reactions with diol substrates.5a
We therefore investigated the new procedure to assess its
potential for kinetic discrimination leading to the selective
esterification of diol substrates (Scheme 3). To this end the
Scheme 3.

D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
Table 2. Reaction of anthranilate esters with methyl succinic anhydride
5957
which is in agreement literature values.19 Benzyl 2-(3-
methyl-2,5-dioxopyrrolidin-1-yl)benzoate 29 was syn-
thesised using standard procedure given in Section 1.3 to
give data which is in agreement literature values.13a All
reactions were conducted in flame-dried or oven-dried
glassware under a dry nitrogen atmosphere unless otherwise
noted. Tetrahydrofuran was dried over sodium/benzo-
phenone and distilled prior to use. Flash chromatography
was performed using Merck Kieselgel 60 (230–400 mesh)
with the indicated solvents. Thin layer chromatography
(TLC) was carried out on precoated silica plates (Merck
Kieselgel 60F254) and compounds were visualized by UV
fluorescence or by staining with vanillin in methanolic
sulfuric acid and heating. Infrared spectra were recorded
with a Perkin Elmer 1600 series Fourier-transform infrared
spectrometer as thin films between sodium chloride plates.
Entry
Anthranilate ester
Succinimide (yield %)
1
Absorption maxima are expressed in wavenumbers (cm21
)
16
17
19
27 (96%)
with the following abbreviations: s¼strong, m¼medium,
w¼weak and br¼broad. H and 13C NMR spectra were
1
obtained using a Bruker AC 200B or a Bruker AM 400
spectrometer. All chemical shifts are given in parts per
million (ppm) downfield from tetramethylsilane as internal
standard (1H) or relative to CDCl3 (13C) and J values are
2
1
given in Hz. H NMR data are tabulated as s, singlet; d,
28 (91%)
doublet; t, triplet; q, quartet, m, multiplet, br, broad. High-
resolution mass spectra were recorded using a VG70-SE
spectrometer operating at nominal accelerating voltage of
70 eV. Chemical ionisation (CI) mass spectra were obtained
with ammonia as the reagent gas.
3
1.1.1. Ethyl (1R p,5R p)-3-ethyl-9-oxo-3-azabicyclo-
[3.3.1]nonane-1-carboxylate 11.17d A mixture of ethyl
2-oxo-cyclohexane-1-carboxylate (5.60 g, 32.9 mmol),
ethylamine (1.48 g, 32.9 mmol, 40% aq. v/v) and formal-
dehyde (1.97 g, 65.8 mmol, 36% aq. v/v) in ethanol
(500 ml) was heated under reflux for 30 h. After removal
of the solvent at reduced pressure, the oily orange residue
was dissolved in ether (200 ml) and extracted with 2 M
hydrochloric acid (3£80 ml). The aqueous extract was made
basic with 10% sodium hydroxide then extracted with ether
(3£150 ml) and dried over anhydrous sodium sulfate. The
solvent was removed at reduced pressure and the resultant
dark orange oil was purified by flash chromatography (19:1
hexane–ethyl acetate) to afford the title compound 11
(2.10 g, 27%) as a bright yellow oil. nmax(NaCl)/cm21 1738
(CvO, ester), 1718 (CvO, ketone); dH (400 MHz; CDCl3)
1.07 (3H, t, J¼7.2 Hz, NCH2CH3), 1.25 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.45–1.53 (1H, m, 7B-H), 1.98–2.29 (3H, m,
6-CH2, 8A-H), 2.35–2.54 (5H, m, 4B-H, 5-H, 8B-H,
NCH2CH3), 2.76–2.87 (1H, m, 7A-H), 2.89 (1H, d,
Jgem¼11.4 Hz, 2B-H), 3.11 (1H, ddd, J4A,5¼2.2 Hz,
J4A,2A¼2.2 Hz, Jgem¼11.0 Hz, 4A-H), 3.18 (1H, dd,
J2A,4A¼2.2 Hz, Jgem¼11.4 Hz, 2A-H), 4.17 (2H, q,
J¼7.2 Hz, OCH2CH3); dC (100 MHz; CDCl3) 12.6 (CH3,
NCH2CH3), 14.0 (CH3, OCH2CH3), 20.4 (CH2, C-7), 34.0
(CH2, C-6), 36.7 (CH2, C-8), 47.1 (CH, C-5), 51.0 (CH2,
NCH2CH3), 58.7 (quat., C-1), 59.8 (CH2, C-4), 60.9 (CH2,
OCH2CH3), 61.5 (CH2, C-2), 171.1 (quat., OCvO), 212.6
(quat., C-9); m/z (EI) 239 (Mþ, 13), 224 (M2CH3, 17), 222
(100), 210 (M2C2H5, 7), 196 (64), 194 (M2OC2H5, 32).
29a (73%)
4
20
30 (84%)
5
22
31 (70%)
6
23
See Ref. 13a.
32 (70%)
a
1. Experimental
1.1. General details
1.1.2. Ethyl (1S p,5S p)-3-ethyl-9-methylidene-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate 12. n-BuLi (5.3 ml,
tert-Butyl 2-aminobenzoate 24 was synthesised using
standard procedure given in Section 1.2 to give data

5958
D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
8.48 mmol, 1.6 M solution in hexane) was added dropwise
to a suspension of methyltriphenylphosphonium bromide
(4.06 g, 11.37 mmol) in dry THF (40 ml) at 278 8C. The
reaction mixture was stirred at 0 8C for 10 min then cooled
to 278 8C and ethyl (1R p,5R p)-3-ethyl-9-oxo-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate 11 (680 mg, 2.84
mmol) in dry THF (10 ml) added dropwise. The reaction
mixture was allowed to warm to room temperature and
stirred for 1 h. The reaction was quenched with distilled
water (10 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
(250 ml) then extracted with ether (3£100 ml) then dried
(MgSO4) and concentrated in vacuo to leave the crude
product which was purified by flash chromatography (19:1
hexane–ethyl acetate) to give the title compound 12
(624 mg, 92%) as a pale yellow oil. nmax(NaCl)/cm21
2915 (CH), 1728 (CvO), 1651 (CvC), 1452, and 1252; dH
(200 MHz; CDCl3) 1.00 (3H, t, J¼7.2 Hz, NCH2CH3), 1.19
(3H, t, J¼7.1 Hz, OCH2CH3), 1.36–1.82 (1H, m, 7B-H),
1.66–1.89 (3H, m, 6-CH2 and 8A-H), 2.03–2.26 (4H, m,
5-H, 8B-H and NCH2), 2.31–2.34 (1H, m, 4B-H), 2.42–
2.49 (1H, dd, J2B,4B¼1.7 Hz, Jgem¼10.7 Hz, 2B-H), 2.59–
2.74 (1H, m, 7A-H), 2.87–2.99 (2H, m, 2A-H and 4A-H),
4.09 (2H, q, J¼7.1 Hz, OCH2), 4.38 (1H, d, J¼0.8 Hz, 10A-
H) and 4.65 (1H, br s, 10B-H); dC (100 MHz; CDCl3) 12.4
(CH3, NCH2CH3), 14.0 (CH3, OCH2CH3), 21.2 (CH2, C-7),
33.3 (CH2, C-6), 35.6 (CH2, C-8), 40.8 (CH, C-5), 50.3
(quat., C-1), 51.8 (CH2, NCH2CH3), 60.1 (CH2, OCH2CH3),
60.4 (CH2, C-4), 61.8 (CH2, C-2), 103.2 (CH2, C-10), 152.0
(quat., C-9) and 174.1 (quat., OCvO); m/z (EI) 237 (Mþ,
50%), 222 (M2CH3, 73), 208 (M2CH3CH2, 50), 164
(M2CH3CH2OCO, 69) and 58 (100). Found: Mþ 237.1743.
C14H23NO2 requires Mþ 237.1743.
62), 178 (M2OH, 34), 164 (M2CH2OH, 18) and 72 (100).
Found: Mþ 195.1634. C12H21NO requires Mþ 195.1623.
1.1.4. Ethyl (1R p,5R p,9R p)-3-ethyl-9-hydroxy-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate 14 and ethyl
(1R p,5R p,9S p)-3-ethyl-9-hydroxy-3-azabicyclo[3.3.1]-
nonane-1-carboxylate 13. A solution of ethyl (1R p,5R p)
3-ethyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate 11
(3.00 g, 12.54 mmol) in THF (15 ml) was added dropwise to
a solution of sodium borohydride (0.24 g, 6.27 mmol) in
THF (15 ml) and water (15 ml) at 0 8C and the mixture
stirred for 30 min. The reaction mixture was then allowed to
warm to room temperature and stirred for a further 2 h. After
this time the reaction was quenched by the addition of 2.5 M
NaOH (20 ml) and the volatile solvents removed in vacuo.
The remaining aqueous mixture was extracted with diethyl
ether (3£50 ml), the combined ether layers washed with
brine (100 ml) then dried (Na2SO4) and concentrated in
vacuo to give a residue which was purified by flash
chromatography (4:1 hexane–ethyl acetate) to give:
(i) ethyl (1R p,5R p,9R p)-3-ethyl-9-hydroxy-3-azabicyclo-
[3.3.1]nonane-1-carboxylate 14 (Rf 0.4) (1.36 g, 45%).
n
max(NaCl)/cm21 3527 (OH) and 1707 (CvO, ester); dH
(400 MHz; CDCl3) 1.03 (3H, t, J¼6.9 Hz, NCH2CH3), 1.25
(3H, t, J¼7.1 Hz, OCH2CH3), 1.45–1.46 (2H, m, 6B-H and
7B-H), 1.74–1.79 (1H, m, 8B-H), 1.94–2.09 (4H, m, 4B-H,
5-H, 6A-H and 8A-H), 2.20 (2H, q, J¼7.1 Hz, NCH2CH3),
2.22–2.25 (1H, m, 2B-H), 2.57–2.61 (1H, m, 7A-H), 2.93
(1H, d, Jgem¼11.0 Hz, 4A-H), 3.15 (1H, d, Jgem¼11.0 Hz,
2A-H), 3.47 (1H, br s, OH), 3.87 (1H, s, 9-H) and 4.15 (2H,
q, J¼7.1 Hz, OCH2CH3); dC (100 MHz; CDCl3) 12.7 (CH3,
NCH2CH3), 14.0 (CH3, OCH2CH3), 20.8 (CH2, C-7), 23.5
(CH2, C-6), 27.5 (CH2, C-8), 34.6 (CH, C-5), 46.7 (quat.,
C-1), 51.9 (CH2, NCH2CH3), 58.2 (CH2, C-4), 59.1 (CH2,
C-2), 60.7 (CH2, OCH2CH3), 71.8 (CH, C-9) and 177.0
(quat., OCvO); m/z (EI) 241 (Mþ, 40%), 224 (M2CH3,
40), 224 (M2OH, 14), and 72 (100). Found: Mþ 241.16743.
C13H23NO3 requires Mþ 241.16780; (ii) ethyl (1R p,5R p,
9S p)-3-ethyl-9-hydroxy-3-azabicyclo[3.3.1]nonane-1-car-
boxylate 13 (Rf 0.28) (1.09 g, 36%). nmax(NaCl)/cm21 3508
(OH) and 1728 (CvO, ester); dH (400 MHz; CDCl3) 1.04
(3H, t, J¼7.1 Hz, NCH2CH3), 1.25 (3H, t, J¼7.1 Hz,
OCH2CH3), 1.40–1.46 (1H, m 7B-H), 1.74–1.79 (1H, m,
6B-H), 1.93–2.09 (3H, m, 6A-H and 8-CH2), 2.17–2.24
(1H, m, 5-H), 2.25 (2H, q, J¼7.1 Hz, NCH2CH3), 2.30–
2.66 (3H, m, 2B-H, 4B-H and 7A-H), 2.94 (1H, d,
Jgem¼11.0 Hz, 4A-H), 3.15 (1H, d, Jgem¼11.0 Hz, 2A-H),
3.47 (1H, br, OH), 3.87 (1H, br s, 9-H) and 4.13 (2H, q,
J¼7.1 Hz, OCH2CH3); dC (100 MHz; CDCl3) 12.5 (CH3,
NCH2CH3), 14.1 (CH3, OCH2CH3), 20.7 (CH2, C-7), 31.0
(CH2, C-6), 34.4 (CH2, C-8), 35.2 (CH, C-5), 48.1 (quat.,
C-1), 51.6 (CH2, NCH2CH3), 52.2 (CH2, C-4), 53.4 (CH2,
C-2), 60.6 (CH2, OCH2CH3), 71.6 (CH, C-9) and 176.4
(quat., OCvO); m/z (EI) 241 (Mþ, 27%), 224 (M2CH3,
100), 224 (M2OH, 8), 212 (M2C2H5, 38) and 196
(M2OC2H5, 60. Found: Mþ 241.1672. C13H23NO3 requires
1.1.3. (1S p,5S p)-(3-Ethyl-9-methylidene-3-azabicyclo-
[3.3.1]non-1-yl)methanol 8. To a solution of ethyl
(1S p,5S p)-3-ethyl-9-methyidene-3-azabicyclo[3.3.1]nonane-
1-carboxylate 12 (250 mg, 1.05 mmol) in dry THF (25 ml)
was added lithium aluminium hydride (80 mg, 2.11 mmol)
and the mixture stirred, under an atmosphere of nitrogen, for
10 min. The reaction was then quenched by dropwise
addition of water (10 ml), the volatiles removed in vacuo.
The remaining aqueous mixture 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 give the crude product which was purified by flash
chromatography (1:1 hexane–ethyl acetate) to give the title
compound 8 (191 mg, 94%) as a clear oil. nmax(NaCl)/cm21
3356 (OH), 2914 (CH), 1649 (CvC), 1471, 1451, and 1239;
dH (200 MHz; CDCl3) 1.05 (3H, t, J¼7.2 Hz, NCH2CH3),
1.22–1.48 (2H, m, 6B-H and 7B-H), 1.59–1.74 (1H, m, 8A-
H), 1.82–1.99 (3H, m, 5-H, 6A-H, 8B-H), 2.12–2.17 (1H,
m, 4B-H), 2.26 (2H, q, J¼7.2 Hz, NCH2CH3), 2.34–2.35
(1H, m, 2B-H), 2.56–2.78 (2H, m, 7A-H and 11-OH),
2.92–2.97 (2H, m, 2A-H and 4A-H), 3.44 (2H, m, OCH2),
4.43 (1H, br s, 10A-H) and 4.68 (1H, br s, 10B-H); dC
(50 MHz; CDCl3) 12.5 (CH3, NCH2CH3), 21.3 (CH2, C-7),
34.1 (CH2, C-6), 36.1 (CH2, C-8), 41.8 (quat., C-1), 41.9
(CH, C-5), 52.1 (CH2, NCH2CH3), 60.5 (CH2, C-4), 62.3
(CH2, C-2), 68.8 (CH2, OCH2), 101.0 (CH2, C-10) and
155.0 (quat., C-9); m/z (EI) 195 (Mþ, 13%), 180 (M2CH3,
M
þ 241.1678.
1.1.5. (1S p,5R p,9R p)-3-Ethyl-1-hydroxymethyl-3-aza-
bicyclo[3.3.1]nonan-9-ol 10. To a solution of (1R p,5R p)-
ethyl 3-ethyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxy-
late 11 (200 mg, 0.836 mmol) in dry THF (20 ml) was
added lithium aluminium hydride (63 mg, 1.67 mmol) and

D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
5959
the mixture stirred, under an atmosphere of nitrogen, for 1 h.
The reaction was then quenched by the dropwise addition of
water (10 ml) and the volatiles 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 (Na2SO4) and concentrated in
vacuo. The crude product was then purified by flash
chromatography (9:1 dichloromethane–methanol) to give
the title compound 10 (90 mg, 54%) as a clear oil.
(1R p,5R p,9R p)-3-ethyl-9-methoxy-3-azabicyclo[3.3.1]-
nonane-1-carboxylate 15 (546 mg, 2.14 mmol) in dry THF
(10 ml) was added dropwise to a solution of lithium
aluminium hydride (162 mg, 4.26 mmol) in THF (20 ml)
and the mixture stirred, under an atmosphere of nitrogen, for
2 h. The reaction was then quenched by dropwise addition
of water (20 ml), the volatiles removed in vacuo. The
remaining aqueous mixture was extracted with ethyl acetate
(2£20 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 (1:1 hexane–ethyl acetate) to give the title
compound 9 (413 mg, 91%) as a clear oil. nmax(NaCl)/cm21
3435 (OH) and 2947 (C–H); dH (200 MHz; CDCl3) 0.99
(3H, t, J¼7.1 Hz, NCH2CH3), 1.22–1.34 (2H, m, 6B-H and
7B-H), 1.37–1.45 (2H, m, 6A-H and 8B-H), 1.64–1.80
(2H, m, 5-H and 8A-H), 1.85–2.03 (2H, m, 2B-H and 4B-H)
2.13 (2H, q, J¼7.1 Hz, NCH2CH3), 2.42–2.67 (1H, m, 7A-
H), 2.61 (1H, d, Jgem¼10.3 Hz, 4A-H), 2.97 (1H, d,
Jgem¼8.4 Hz, 2A-H), 3.14 (1H, d, J¼3.1 Hz, 9-H), 3.29
(3H, s, OCH3) and 3.24–3.28 (3H, m, OH and CH2OH); dC
(50 MHz; CDCl3) 12.6 (CH3, NCH2CH3), 20.4 (CH2, C-7),
23.9 (CH2, C-6), 27.1 (CH2, C-8), 30.6 (CH, C-5), 38.1
(quat., C-1), 52.1 (CH2, NCH2CH3), 55.0 (CH3, OCH3),
58.0 (CH2, C-4), 60.9 (CH2, C-2), 70.6 (CH2, OCH2OH) and
84.5 (CH, C-9); m/z (EI) 213 (Mþ, 28%), 198 (M2CH3, 59),
224 (M2OCH3, 38) and 72 (100). Found: Mþ 213.1729.
C12H23NO2 requires Mþ 213.1729.
n
max(NaCl)/cm21 3355 (OH), 2912 (CH), 1472, 1453,
1069 and 1037; dH (200 MHz; CDCl3) 1.00 (3H, t,
J¼7.2 Hz, NCH2CH3), 1.19–1.28 (2H, m, 6-CH2), 1.38–
1.53 (2H, m, 7B-H and 8A-H), 1.75–2.05 (4H, m, 2B-H,
4B-H, 5-H and 8B-H), 2.16 (2H, q, J¼7.2 Hz, NCH2CH3),
2.48–2.54 (1H, m, 7A-H), 2.61 (1H, d, Jgem¼12.2 Hz, 4A-
H), 2.96 (1H, d, Jgem¼11.1 Hz, 2A-H), 3.29–3.45 (3H, m,
OCH2 and OH), 3.68 (1H, d, J¼3.2 Hz, 9-H) and 3.71 (1H,
br, 9-OH); dC (50 MHz; CDCl3) 12.7 (CH3, NCH2CH3),
20.6 (CH2, C-7), 23.9 (CH2, C-6), 26.6 (CH2, C-8), 36.0
(CH, C-5), 37.9 (quat., C-1), 52.3 (CH2, NCH2CH3), 58.4
(CH2, C-4), 60.5 (CH2, C-2), 70.6 (CH2, OCH2), and 74.9
(CH, C-9); m/z (EI) 199 (Mþ, 28%), 184 (M2CH3, 47), 182
(M2OH, 18) and 72 (100). Found: Mþ 199.1571.
C11H21NO2 requires Mþ 199.1572.
1.1.6. Ethyl (1R p,5R p,9R p)-3-ethyl-9-methoxy-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate 15. To a suspension
of sodium hydride (132 mg, 60% in oil, 3.32 mmol) in dry
THF (10 ml) at 0 8C was added a solution of ethyl
(1R p,5R p,9R p)-3-ethyl-9-hydroxy-3-azabicyclo[3.3.1]-
nonane-1-carboxylate 14 (200 mg, 0.83 mmol) in dry THF
(10 ml). The mixture was then stirred for 1 h after which
time iodomethane (0.70 g, 0.32 ml, 5.00 mmol) was added
and the mixture was stirred at room temperature for 72 h.
The reaction was then quenched by the careful addition of
water (25 ml). The volatile solvents were removed in vacuo
and the remaining aqueous solution extracted with ethyl
acetate (3£20 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 ethyl (1R p,5R p,9R p)-3-ethyl-9-methoxy-3-
azabicyclo[3.3.1]nonane-1-carboxylate 15 (Rf 0.4) (148 mg,
70%) as a clear oil. nmax(NaCl)/cm21 2927 (C–H), 1731
(CvO, ester) and 1259 (C–O); dH (200 MHz; CDCl3) 0.97
(3H, t, J¼7.1 Hz, NCH2CH3), 1.19 (3H, t, J¼7.1 Hz,
OCH2CH3), 1.35–1.51 (2H, m, 6B-H and 7B-H), 1.70–1.80
(2H, m, 6A-H and 8B-H), 1.98–2.04 (2H, m, 5-H and 8A-
H), 2.13–2.25 (4H, m, 2B-H, 4B-H and NCH2CH3), 2.44–
2.54 (1H, m, 7A-H), 2.85 (1H, d, Jgem¼10.8 Hz, 4A-H),
2.96 (1H, d, Jgem¼11.1 Hz, 2A-H), 3.26 (3H, s, OCH3), 3.47
(1H, d, J¼3.6 Hz, 9-H) and 4.01–4.12 (2H, m, OCH2CH3);
dC (50 MHz; CDCl3) 12.6 (CH3, NCH2CH3), 14.0 (CH3,
OCH2CH3), 20.5 (CH2, C-7), 23.6 (CH2, C-6), 26.5 (CH2,
C-8), 30.8 (CH, C-5), 46.9 (quat., C-1), 51.8 (CH2,
NCH2CH3), 55.9 (CH3, OCH3), 58.1 (CH2, C-4), 60.1
(CH2, C-2), 61.3 (CH2, OCH2CH3), 81.4 (CH, C-9) and
175.2(quat., OCvO);m/z(EI)255(Mþ, 32%), 240(M2CH3,
44), 226(M2C2H5, 30) and 224 (M2OCH3, 100). Found:Mþ
255.1845. C14H25NO3 requires Mþ 255.1834.
1.1.8. N-(Trifluoroacetyl)anthranilic acid 6. Anthranilic
acid (15.13 g, 0.11 mol) was carefully added in portions over
15 min to a 250 ml round bottom flask containing vigourously
stirred trifluoroacetic anhydride (30.7 ml, 0.22 mol). After 1 h
the mixture was cooled to 0 8C and carefully quenched by the
addition of water (100 ml). The mixture was then filtered and
the crude product recystallised from ethanol/water to give the
title compound 6 (18.77 g, 73%) as colourless crystals, mp
178–180 8C (lit.19 mp 179–182 8C).
1.2. Standard procedure for the formation of 2-amino-
benzoate esters using N-(trifluoroacetyl)anthranilic
acid 6
To a solution of alcohol (1 mmol), N-(trifluoroacetyl)-
anthranilic acid 179 (2 mmol) and 4-(dimethylamino)-
pyridine (0.1 mmol) in acetonitrile (5 ml) was added 1,3-
dicyclohexylcarbodiimide (2 mmol) and the mixture stirred,
under an atmosphere of nitrogen, at 40 8C for 24 h. After
this time the mixture was cooled, filtered and the filtrate
evaporated to dryness. The crude mixture 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
(2 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 to
afford the anthranilate ester.
1.1.7. (1R p,5S p,9R p)-(3-Ethyl-9-methoxy-3-aza-
bicyclo[3.3.1]non-1-yl)methanol 9.17d A solution of ethyl

5960
D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
1.2.1. 1-Methyl-piperidin-3-ylmethyl 2-aminobenzoate
16. This reaction was carried out according to the standard
procedure using 1-methyl-3-piperidinemethanol 7 (50 mg,
0.39 mmol), N-(trifluoroacetyl)anthranilic acid 6 (180 mg,
0.77 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol),
1,3-dicyclohexylcarbodiimide (160 mg, 0.77 mmol) and
sodium borohydride (29 mg, 0.77 mmol) using 5:1 dichloro-
methane–methanol as solvent for flash chromatography to
afford the title compound 16 (78 mg, 81%) as a cream solid,
mp 51–52 8C. nmax(NaCl)/cm21 3480 and 3369 (NH2), 1686
(CvO), 1618, 1589, 1560, 1456, 1296 and 1245; dH
n
max(NaCl)/cm21 3483 and 3372 (NH2), 2957 (C–H), 1690
(CvO), 1617, 1589, 1560, 1371, 1293, 1245, 1161 and
1105; dH (200 MHz; CDCl3) 1.03 (9H, br s, 3£20-CH3), 3.96
(2H, s, 10-CH2), 5.55 (2H, br, NH2), 6.62–6.70 (2H, m, 3-H
and 5-H), 7.26 (1H, t, J¼7.7 Hz, 4-H) and 7.89 (1H, d,
J¼8.3 Hz, 6-H); dC (50 MHz; CDCl3) 26.6 (CH3, 20-CH3),
31.5 (quat., C-20), 73.6 (CH2, C-10), 111.4 (quat., C-1), 116.6
(CH, C-3), 116.9 (CH, C-5), 131.0 (CH, C-6), 133.9 (CH,
C-4), 149.9 (quat., C-2) and 168.0 (quat., OCvO); m/z (EI)
207 (Mþ, 71%), 120 (M2C5H11O, 98), 119 (M2C5H12O,
98), 92 (M2C6H11O2, 100). Found: Mþ 207.1261.
C12H17NO2 requires Mþ 207.1259.
0
0
(400 MHz; CDCl3) 1.07 (1H, ddd, J4 A,5 A-H¼4.5 Hz,
J4 A,5 B¼4.5 Hz, Jgem¼11.4 Hz, 40A-H), 1.55–1.82 (4H, m,
0
0
20A-H, 40B-H and 50-CH2), 1.91 (1H, td, Jgem¼11.2 Hz,
1.2.4. Benzyl 2-aminobenzoate 19.16b The reaction was
carried out according to the standard procedure using benzyl
alcohol (500 mg, 4.62 mmol), N-(trifluoroacetyl)anthranilic
acid 6 (2.15 g, 9.23 mmol), 4-(dimethylamino)pyridine
(56 mg, 0.46 mmol), 1,3-dicyclohexylcarbodiimide (1.9 g,
9.25 mmol) and sodium borohydride (350 mg, 9.25 mmol)
using 5:1 hexane–ethyl acetate as the solvent for flash
chromatography to afford the title compound 19 (893 mg,
85%) as a pale oil. nmax(NaCl)/cm21 3482 and 3373 (NH2),
3031, 1690 (CvO), 1615, 1587, 1560, 1292 and 1242; dH
(200 MHz; CDCl3) 5.32 (2H, s, 10-CH2), 5.72 (2H, br, NH2),
6.60–6.67 (2H, m, 3-H and 5-H), 7.21 (1H, td, J¼7.7 Hz,
1.4, 4-H), 7.32–7.47 (5H, m, 5£Ar-H) and 7.94 (1H, dd,
J¼8.2 Hz, 1.4, 6-H); dC (50 MHz; CDCl3) 65.8 (CH2,
10-CH2), 110.3 (quat., C-1), 116.0 (CH, C-3), 116.5 (CH,
C-5), 127.8 (CH, Ar), 127.9 (CH, Ar), 128.4 (CH, Ar), 131.1
(CH, C-6), 134.0 (CH, C-4), 136.1 (quat., Ar), 150.4
(quat., C-2) and 167.6 (quat., CvO); m/z (EI) 227 (Mþ,
65%), 150 (M2C6H5, 5), 120 (M2C7H7O, 28) and 91
(C7H7, 100). Found: Mþ 227.0943. C14H13NO2 requires Mþ
227.0946.
J6 A,5 A¼11.2 Hz, J6 A,5 B¼3.0 Hz, 60A-H), 2.03–2.17 (1H, br
m, 30-CH), 2.27 (3H, s, N-CH3), 2.78 (1H, br d, Jgem¼11.2 Hz,
0
0
0
0
60B-H), 2.93 (1H, dt, Jgem¼10.8 Hz, J2 B,3 A¼1.6 Hz,
0
0
J2 B,6 B¼1.6 Hz, 20B-H), 4.06–4.17 (2H, m, OCH2), 5.72
(2H, br, NH2), 6.60–6.64 (2H, m, 3-H and 5-H), 7.24 (1H, t,
J¼7.7 Hz, 4-H) and 7.82 (1H, d, J¼7.5 Hz, 6-H); dC
(100 MHz; CDCl3) 24.7 (CH2, C-50), 26.7 (CH2, C-40), 35.9
(CH, C-30), 46.5 (CH3, N-CH3), 55.9 (CH2, C-60), 59.1 (CH2,
C-20), 66.9 (CH2, OCH2), 110.7 (quat., C-1), 116.2 (CH, C-3),
116.6 (CH, C-5), 131.0 (CH, C-6), 133.9 (CH, C-4), 150.5
(quat., C-2) and 167.9 (quat., CvO); m/z (EI) 248 (Mþ, 82%),
233 (M2CH3, 2), 128 (M2C7H6NO, 65), 120 (C7H6NO, 35),
112 (M2C7H6NO2, 59) and 111 (C7H13N, 100). Found: Mþ
248.1536. C14H20N2O2 requires Mþ 248.1536.
0
0
1.2.2. 3-(Diethylamino)propyl 2-aminobenzoate 17. This
reaction was carried out according to the standard procedure
using 3-(diethylamino)-1-propanol (28 mg, 0.21 mmol),
N-(trifluoroacetyl)anthranilic acid 6 (100 mg, 0.43 mmol),
4-(dimethylamino)pyridine (3 mg, 0.02 mmol), 1,3-dicyclo-
hexylcarbodiimide (89 mg, 0.43 mmol) and sodium
borohydride (16 mg, 0.43 mmol) using 5:1 dichloro-
methane–methanol as solvent for flash chromatography to
afford the title compound 17 (45 mg, 85%) as a pale yellow
oil. nmax(NaCl)/cm21 3477 and 3370 (NH2), 1689 (CvO),
1617, 1588, 1562, 1467 and 1245; dH (400 MHz; CDCl3)
1.07 (6H, t, J¼7.2 Hz, 2£NCH2CH3), 2.00 (2H, quin,
J¼6.3 Hz, 20-CH2), 2.65–2.73 (6H, m, 2£NCH2CH3 and
30-CH2), 4.33 (2H, t, J¼6.3 Hz, 10-CH2), 5.73 (2H, br, NH2),
6.61–6.67 (2H, m, 3-H and 5-H), 7.26 (1H, td, J¼7.1 Hz,
1.6, 4-H) and 7.83 (1H, dd, J¼8.0 Hz, 1.6, 6-H); dC
(50 MHz; CDCl3) 11.2 (CH3, NCH2CH3), 22.9 (CH2, C-20),
46.7 (CH2, NCH2CH3), 49.1 (CH2, C-30), 62.6 (CH2, C-10),
110.7 (quat., C-1), 116.1 (CH, C-3), 116.5 (CH, C-5), 131.0
(CH, C-6), 134.0 (CH, C-4), 150.4 (quat., C-2) and 167.9
(quat., CvO); m/z (EI) 250 (Mþ, 46%), 235 (M2CH3, 31),
221 (M2CH2CH3, 6), 178 (M2N(CH2CH3)2, 11), 120
(M2C7H16NO, 62) and 86 (CH3CH2)2NCH2, 100). Found:
Mþ 250.1699. C14H22N2O2 requires Mþ 250.1681.
1.2.5. (10S p,50S p)-(3-Ethyl-9-methyidene-3-azabicyclo-
[3.3.1]non-1-yl)methyl 2-aminobenzoate 20. The reaction
was carried out according to the standard procedure using
(1S p,5S p)-(3-ethyl-9-methyidene-3-azabicyclo[3.3.1]non-
1-yl)methanol 8 (50 mg, 0.257 mmol), N-(trifluoroacetyl)-
anthranilic acid 6 (120 mg, 0.515 mmol), 4-(dimethyl-
amino)pyridine (3 mg, 0.026 mmol), 1,3-dicyclo-
hexylcarbodiimide (107 mg, 0.518 mmol) and sodium
borohydride (49 mg, 1.29 mmol) using 1:1 hexane–ethyl
acetate as solvent for flash chromatography to afford the
title compound 20 (60 mg, 75%) as a pale yellow oil.
n
max(NaCl)/cm21 3482 and 3373 (NH2), 2919 (CH), 1688
(CvO), 1652 (CvC), 1616, 1589, 1456, 1293 and 1244; dH
(200 MHz; CDCl3) 1.06 (3H, t, J¼7.1 Hz, NCH2CH3),
1.46–2.09 (6H, m, 50-H, 60-CH2, 70B-H and 80-CH2), 2.19–
2.33 (3H, m, 40B-H and NCH2CH3), 2.43–2.44 (1H, m, 20B-
H), 20.74–2.83 (1H, m, 70A-H), 3.00–3.11 (2H, 0m, 20A-H
and 4 A-H), 4.21 (2H, s, OCH2), 4.56 (1H, br s, 10 A-H) and
4.78 (1H, br s, 100B-H), 5.72 (2H, br, NH2), 6.61–6.69 (2H,
m, 3-H and 5-H), 7.22–7.30 (1H, m, 4-H) and 7.85 (1H, dd,
J¼1.6 Hz, 7.5, 6-H); dC (50 MHz; CDCl3) 12.5 (CH3,
NCH2CH3), 21.4 (CH2, C-70), 33.9 (CH2, C-60), 36.4
(CH2, C-80), 40.9 (quat., C-10), 41.7 (CH, C-50), 52.1
(CH2, NCH2CH3), 60.4 (CH2, C-40), 62.8 (CH2, C-20), 69.9
(CH2, OCH2), 101.7 (CH2, C-100), 110.9 (quat., C-1), 116.3
(CH, C-3), 116.7 (CH, C-5), 131.1 (CH, C-6), 134.0 (CH,
C-4), 150.4 (quat., C-2), 155.9 (quat., C-90) and 168.0 (quat.,
CvO); m/z (EI) 314 (Mþ, 31%), 299 (M2CH3, 19), 178
1.2.3. 2,2-Dimethylpropyl 2-aminobenzoate 18. The
reaction was carried out according to the standard procedure
using neopentyl alcohol (90 mg, 1.02 mmol), N-(trifluoro-
acetyl)anthranilic acid 6 (529 mg, 2.27 mmol), 4-(dimethyl-
amino)pyridine (14 mg, 0.113 mmol), 1,3-dicyclo-
hexylcarbodiimide (468 mg, 2.27 mmol) and sodium
borohydride (85 mg, 2.27 mmol) using 6:4 hexane–ethyl
acetate as the solvent for flash chromatography to afford the
title compound 1817d (198 mg, 94%) as a pale yellow oil.

D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
5961
(M2NH2C6H4CO2, 100) and 120 (NH2C6H4CO, 60).
Found: Mþ 314.1979. C19H26N2O2 requires Mþ 314.1994.
(675 mg, 3.27 mmol) and sodium borohydride (123 mg,
3.23 mmol) using 7:3 hexane–ethyl acetate as solvent for
flash chromatography to afford the title compound 23
(335 mg, 85%) as a pale yellow oil. nmax(NaCl)/cm21 3485
and 3373 (NH2), 3031, 2980, 1687 (CvO), 1616, 1560,
1487, 1292 and 1240; dH (200 MHz; CDCl3) 1.65 (3H, d,
J¼6.7 Hz, 20-CH3), 5.44 (2H, br, NH2), 6.07 (1H, q,
J¼6.7 Hz, 10-CH), 6.62–6.70 (2H, m, 3-H and 5-H),
7.22–7.46 (6H, m, 5£Ar-H and 4-H) and 7.98 (1H, d0d,
J¼8.4 Hz, 1.8, 6-H); dC (50 MHz; CDCl3) 22.6 (CH3, C-2 ),
72.1 (CH, C-10), 110.7 (quat., C-1), 116.2 (CH, C-3), 116.6
(CH, C-5), 125.9 (CH, Ar), 127.7 (CH, Ar), 128.5 (CH, Ar),
131.2 (CH, C-6), 134.1 (CH, C-4), 142.0 (quat., Ar), 150.4
(quat., C-2) and 167.2 (quat., CvO); m/z (EI) 241 (Mþ,
50%), 150 (M2C7H7, 73), 120 (C7H6NO, 41) and 105
(C6H5CO, 33). Found: Mþ 241.1102. C15H15NO2 requires
Mþ 241.1103.
1.2.6. (10S p,50R p,90R p)-(3-Ethyl-9-methoxy-3-aza-
bicyclo[3.3.1]non-1-yl)methyl 2-aminobenzoate 21.17d
The reaction was carried out according to the standard
procedure using (1R p,5S p,9R p)-(3-ethyl-9-methoxy-1-3-
azabicyclo[3.3.1]non-1-yl)methanol 9 (258 mg, 1.19 mmol),
N-(trifluoroacetyl)anthranilic acid 6 (556 mg, 2.39 mmol),
4-(dimethylamino)pyridine (72 mg, 0.60 mmol), 1,3-dicyclo-
hexylcarbodiimide (492 mg, 2.39 mmol) and sodium boro-
hydride (135 mg, 3.58 mmol) using 1:1 hexane–ethyl acetate
as solvent for flash chromatography to afford the title
compound 21 (312 mg, 78%) as a clear oil. nmax (NaCl)/
cm21 3481 and 3371 (NH2), 2969 and 2971 (C–H), 1689
(CvO), 1617, 1588, 1561, 1487, 1455, 1379, 1294 and 1244;
dH (200 MHz; CDCl3) 1.04 (3H, t, J¼7.1 Hz, NCH2CH3),
1.21–1.57 (3H, m, 70B-H and 60-CH2), 1.62–1.95 (2H, m, 80-
CH2), 2.05–2.30 (5H, m, 20B-H, 40B-H, 50-H and NCH2CH3),
2.54–2.67 (1H, m, 70A-H), 2.94 (1H, d, Jgem¼11.0 Hz, 40A-
H), 3.06 (1H, d, Jgem¼10.2 Hz, 20A-H), 3.16 (1H, br s, 9-H),
3.31 (3H, s, OCH3), 4.05 (2H, m, OCH2), 5.75 (2H, br, NH2),
6.62–6.69 (2H, m, 3-H and 5-H), 7.26 (1H, td, J¼7.2 Hz, 0.8.
4-H) and 7.85 (1H, dd, J¼1.4 Hz, 8.3, 6-H); dC (50 MHz;
CDCl3) 12.7 (CH3, NCH2CH3), 20.4 (CH2, C-70), 24.3 (CH2,
C-60), 28.0 (CH2, C-80), 30.7 (CH, C-50), 38.2 (quat., C-10),
52.3 (CH2, NCH2CH3), 56.0 (CH3, OCH3), 58.3 (CH2, C-40),
61.4 (CH2, C-20), 69.3 (CH2, OCH2), 81.1 (CH, C-90), 110.9
(quat., C-1), 116.2 (CH, C-3), 116.7 (CH, C-5), 130.9 (CH,
C-6), 133.9 (CH, C-4), 150.5 (quat., C-2) and 168.0 (quat.,
OCvO); m/z (EI) 332 (Mþ, 50%), 317 (M2CH3, 35), 301
(M2OCH3, 30), 196 (M2NH2C6H4CO2, 25), 165
(M2C8H9NO2, 64), 120 (NH2C6H4CO, 59) and 72 (100).
Found: Mþ 332.2094. C19H28N2O3 requires Mþ 332.2099.
1.2.9. (10S p,50S p,90R p)-3-Ethyl-9-hydroxy-3-aza-
bicyclo[3.3.1]non-1-ylmethyl 2-aminobenzoate 25. The
reaction was carried out according to the standard pro
cedure using (1S p,5R p,9R p)-3-ethyl-1-hydroxymethyl-3-
azabicyclo[3.3.1]nonan-9-ol 10 (200 mg, 1.00 mmol),
N-(trifluoroacetyl)anthranilic acid 6 (234 mg, 1.00 mmol),
4-(dimethylamino)pyridine (61 mg, 0.50 mmol), 1,3-
dicyclohexylcarbodiimide (207 mg, 1.00 mmol) and
sodium borohydride (76 mg, 2.01 mmol) using 1:1 hexane–
ethyl acetate as solvent for flash chromatography to afford
the title compound 25 (178 mg, 56%) as a pale yellow oil.
n
max (NaCl)/cm21 3481 (NH) and 3371 (NH and OH), 2969
and 2971 (C–H), 1689 (CvO), 1617, 1588, 1561, 1487,
1455, 1379, 1294 and 1244; dH (200 MHz; CDCl3) 1.09
(3H, t, J¼6.9 Hz, NCH2CH3), 1.34–1.59 (4H, m, 60-CH2,
700B-H and 80A-H), 1.71–2.31 (6H, m, 20B-H,0 40B-H, 50-H,
8 B-H and NCH2CH3), 2.57–2.66 (1H, m, 7 A-H), 2.92–
3.05 (3H, m, 20A-H, 40A-H and 90-OH), 3.51 (1H, br s, 90-H),
3.66 (1H, d, Jgem¼11.5 Hz, OCHAHB), 4.47 (1H, d,
Jgem¼11.5 Hz, OCHAHB), 5.72 (2H, br, NH2), 6.62–6.69
(2H, m, 3-H and 5-H), 7.28 (1H, t, J¼7.3 Hz, 4-H) and 7.85
(1H, d, J¼8.3 Hz, 6-H); dC (50 MHz; CDCl3) 12.8 (CH3,
NCH2CH3), 20.6 (CH2, C-70), 24.1 (CH2, C-60), 27.2 (CH2,
C-80), 35.3 (CH, C-50), 38.8 (quat., C-10), 52.2 (CH2, NCH2-
CH3), 58.7 (CH2, C-40), 60.7 (CH2, C-20), 68.9 (CH2,
OCH2), 71.0 (CH, C-90), 110.2 (quat., C-1), 116.2 (CH,
C-3), 116.7 (CH, C-5), 131.1 (CH, C-6), 134.3 (CH, C-4),
150.7 (quat., C-2) and 168.6 (quat., CvO); m/z (EI) 318
(Mþ, 35%), 303 (M2CH3, 9), 198 (M2NH2C6H4CO, 22),
182 (M2NH2C6H4CO2, 55), 120 (NH2C6H4CO, 35) and 72
(100). Found: Mþ 318.1940. C18H26N2O3 requires Mþ
318.1943. A second fraction afforded (1S p,5R p,9R p)-9-(2-
aminobenzoyl)-3-ethyl-3-azabicyclo[3.3.1]non-1-ylmethyl
2-aminobenzoate 26 (44 mg, 10%) as a yellow oil, for which
the spectroscopic data was in agreement with that reported
in the procedure described below.
1.2.7. Cyclohexyl 2-aminobenzoate 22.23 The reaction was
carried out according to the standard procedure, with the
esterification step being left for 48 h, using cyclohexanol
(200 mg, 2.0 mmol), N-(trifluoroacetyl)anthranilic acid 6
(920 mg, 3.94 mmol), 4-(dimethylamino)pyridine (24.0 mg,
0.196 mmol), 1,3-dicyclohexylcarbodiimide (812 mg,
3.94 mmol) and sodium borohydride (75 mg, 1.98 mmol)
using 1:1 hexane–ethyl acetate as solvent for flash
chromatography to afford the title compound 22 (426 mg,
97%) as a clear oil. nmax (NaCl)/cm21 3479 and 3369
(NH2), 2935 and 2858 (C–H), 1686 (CvO), 1615; dH
(200 MHz; CDCl3) 1.28–1.93 (10H, m, 5£CH2), 4.98–5.06
(1H, m, 10-H), 5.61 (2H, br, NH2), 6.62–6.70 (2H, m, 3-H
and 5-H), 7.26 (1H, t, J¼7.7 Hz, 4-H), 7.91 (1H, d,
J¼8.2 Hz, 6-H); dC (50 MHz; CDCl3) 23.5 (CH2, C-30),
25.3 (CH2, C-40), 31.5 (CH2, C-20), 72.1 (CH, C-10), 111.3
(quat., C-1), 116.0 (CH, C-3), 116.5 (CH, C-5), 131.0 (CH,
C-6), 133.7 (CH, C-4), 150.2 (CH, C-2), 167.4 (quat.,
OCvO); m/z (EI) 219 (Mþ, 43%), 137 (M2C6H10, 94) and
119 (M2C6H12O, 100). Found: Mþ 219.1259. C13H17NO2
requires Mþ 219.1259.
1.2.10. (10S p,50R p,9R p)-9-(2-Aminobenzoyl)-3-ethyl-3-
azabicyclo[3.3.1]non-1-lymethyl 2-aminobenzoate 26.
The reaction was carried out according to the standard
procedure using (1S p,5R p,9R p) 3-ethyl-1-hydroxymethyl-
3-azabicyclo[3.3.1]nonan-9-ol 10 (50 mg, 0.250 mmol),
N-(trifluoroacetyl)anthranilic acid 6 (120 mg, 0.515 mmol),
4-(dimethylamino)pyridine (3 mg, 0.026 mmol), 1,3-dicyclo-
hexylcarbodiimide (107 mg, 0.519 mmol) and sodium
1.2.8. 1-Phenylethyl 2-aminobenzoate 23. The reaction
was carried out according to the standard procedure, with
the esterification step being left for 48 h, using 1-phenyl-
ethanol (200 mg, 1.63 mmol), N-(trifluoroacetyl)anthranilic
acid 6 (763 mg, 3.27 mmol), 4-(dimethylamino)pyridine
(20 mg,
0.163 mmol),
1,3-dicyclohexylcarbodiimide

5962
D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
borohydride (49 mg, 1.29 mmol) using 1:1 hexane–ethyl
acetate as solvent for flash chromatography to afford the title
compound26(52 mg, 48%)as a yellow oil. nmax (NaCl)/cm21
3483 and 3373 (NH2), 2924 and 2779 (C–H), 1687 (CvO),
1616, 1588, 1561, 1487, 1454, 1383, 1294 and 1242; dH
(200 MHz; CDCl3) 1.07 (3H, t, J¼7.1 Hz, NCH2CH3), 1.57–
2.05 (5H, m, 60-CH2, 70B-H and 80-CH2), 2.15–2.42 (5H, m,
20B-H, 40B-H, 50-H and NCH2CH3), 2.65–2.86 (1H, m, 70A-
H), 3.05 (2H, m, 20A-H and 40A-H), 3.99–4.12 (2H, m,
OCH2), 5.11 (1H, d, J¼3.5 Hz, 90-H), 5.60–5.80 (4H, br,
NH2), 6.61–6.70 (4H, m, 2£3-H and 2£5-H), 7.21–7.31 (2H,
m, 2£4-H) and 7.85–7.96 (2H, m, 2£6-H); dC (50 MHz;
CDCl3) 12.7 (CH3, NCH2CH3), 20.5 (CH2, C-70), 25.0 (CH2,
C-60), 28.5 (CH2, C-80), 33.2 (CH, C-50), 37.7 (quat., C-10),
52.0 (CH2, NCH2CH3), 57.9 (CH2, C-40), 61.1 (CH2, C-20),
68.7 (CH2, OCH2), 74.3 (CH, C-90), 110.6 and 110.8 (quat.,
2£C-1), 116.2 (CH, 2£C-3), 116.5 and 116.6 (CH, 2£C-5),
130.9 and 131.0 (CH, 2£C-6), 133.9 and 134.0 (CH, 2£C-4),
150.4 and 150.6 (quat., 2£C-2) and 167.1 and 167.7 (quat.,
2£OCvO); m/z (EI) 437 (Mþ, 11%), 317 (M2NH2C6H4CO,
5), 300 (M2NH2C6H4CO2, 58), 164 [M22£(NH2C6H4CO2),
100] and 120 (NH2C6H4CO2, 92). Found: Mþ 437.2315.
C25H31N3O4 requires Mþ 437.2315.
216 (M2C7H14NO, 36), 188 (M2C8H14NO2, 40), 128
(C8H14NO2, 81) and 41 (100). Found: Mþ 344.1734.
C19H24N2O4 requires Mþ 344.1736.
1.3.2. 3-(Diethylamino)propyl 2-(3-methyl-2,5,dioxo-
pyrrolidin-1-yl)benzoate 28. The reaction was carried out
according to the standard procedure using 3-(diethyl-
amino)propyl 2-aminobenzoate 17 (300 mg, 1.198 mmol)
and methylsuccinic anhydride (410 mg, 3.595 mmol) using
4:1 dichloromethane–methanol as solvent for flash chro-
matography to afford the title compound 28 (377 mg, 91%)
as a yellow oil. nmax (NaCl)/cm21 1777 (N–CvO), 1713
(CvO) and 1573; dH (200 MHz; CDCl3) 1.11 (6H, br t,
2£NCH2CH3), 1.30 (3H, br d, 30-CH3), 1.94 (2H, m, 200-
CH2), 2.31–2.46 (2H, m, 40-CH2), 2.55–2.64 (1H, m, 30-H),
2.90–3.01 (6H, m, 2£NCH2CH3 and 300-CH2), 4.19 (2H, br
t, 100-CH2), 7.14 (1H, dd, J¼1.0 Hz, 7.8, 3-H), 7.40 (1H, td,
J¼7.6 Hz, 1.3, 5-H), 7.54 (1H, td, J¼7.6 Hz, 1.6, 4-H) and
7.92 (1H, dd, J¼1.4 Hz, 7.7, 6-H); dC (50 MHz; CDCl3) 8.1
(CH3, 2£NCH2CH3), 16.9 (CH3, 30-CH3), 23.0 (CH2, C-200),
36.4 (CH2, C-40), 36.7 (CH, C-30), 45.9 (CH2,
2£NCH2CH3), 48.2 (CH2, C-300), 61.8 (CH2, C-100), 126.6
(quat., C-1), 129.0 (CH, C-5), 129.2 (CH, C-3), 130.7 (CH,
C-6), 132.1 (quat., C-2), 133.2 (CH, C-4), 164.0 (quat.,
OCvO), 177.3 (quat., C-500) and 179.6 (quat., C-20); m/z
(EI) 346 (Mþ, 5%), 331 (M2CH3, 30), 274 (M2(C2H5)2N,
4), 188 (M2C8H16NO2, 27) and 86 (C5H12N, 100). Found:
1.3. Standard procedure for the formation of 2-(3-
methyl-2,5-dioxopyrrolidin-1-yl)benzoate esters using
methylsuccinic anhydride
M
þ 346.1882. C19H26N2O4 requires Mþ 346.1893.
2-Aminobenzoate ester (1 mmol) and methylsuccinic
anhydride (3 mmol) were heated together at 125 8C for
3 h. After this time the crude mixture was dissolved in warm
ethyl acetate (10 ml), washed with sat. sodium bicarbonate
solution (30 ml) and brine (30 ml) then dried (MgSO4) and
concentrated in vacuo. The crude product was purified by
flash chromatography to afford the 2-(3-methyl-2,5-dioxo-
pyrrolidin-1-yl)benzoate ester.
1.3.3. (100S p,500S p,30R p)- and (100 S p,500 S p,300S p)-(3-Ethyl-
9-methyidene-3-azabicyclo[3.3.1]non-1-yl)methyl 2-(3-
methyl-2,5-dioxopyrrolidin-1-yl)benzoate
reaction was0carried out according to the standard procedure
using
(1 S p,50S p)-(3-ethyl-9-methyidene-3-azabicyclo-
30.
The
[3.3.1]non-1-yl)methyl 2-aminobenzoate 20 (45 mg,
0.143 mmol) and methylsuccinic anhydride (48 mg,
0.429 mmol) using 7:3 hexane–ethyl acetate as solvent
for flash chromatography to afford the title compound 30
(49 mg, 84%) as a clear oil. nmax(NaCl)/cm21 2920 (C–H),
1779 (N–CvO), 1715 (CvO), 1602, 1492, 1262 and 1186;
dH (200 MHz; CDCl3) 1.21 (3H, t, J¼7.2 Hz, NCH2CH3),
1.38–1.62 (4H, m, 30-CH3 and 600 B-H), 1.68–2.10 (4H, m,
600 A-H, 700 B-H and 800-CH2), 2.15–2.16 (1H, m, 500-H),
2.20–2.30 (4H, m, 200 B-H, 400 B-H and NCH2CH3), 2.42–
2.79 (30H0 , br m, 30-H, 400 A-H and 700 A-H), 3.00–3.09 (3H,
br m, 2 A-H and 40-CH2), 4.15 (2H, s, OCH2), 4.49 (1H, br
s, 1000 A-H), 4.75 (1H, br s, 1000 B-H), 7.24 (1H, dd,
J¼0.9 Hz, 7.7, 3-H) 7.51 (1H, td, J¼7.7 Hz, 1.3, 5-H), 7.64
(1H, td, J¼7.7 Hz, 1.5, 4-H) and 8.10 (1H, dd, J¼1.0 Hz,
7.7, 6-H); dC (50 MHz; CDCl3) 12.5 (CH3, NCH2CH3), 16.3
(CH3, 30-CH3), 21.4 (CH2, C-700), 33.9 (CH2, C-600), 35.2
(CH2, C-40), 36.8 (CH2, C-800), 36.9 (CH, C-30), 40.9 (quat.,
C-100), 41.7 (CH, C-500), 52.0 (CH2, NCH2CH3), 60.4 (CH2,
C-400), 62.8 (CH2, C-200), 70.7 (CH2, OCH2), 101.6 (CH2, C-
1000), 126.3 (quat., C-1), 129.2 (CH, C-5), 129.3 (CH, C-3),
129.8 (CH, C-6), 131.4 (quat., C-2), 133.4 (CH, C-4), 0156.9
(quat., C-900), 164.5 (quat., OCvO), 176.0 (quat., C-5 ) and
179.4 (quat., C-20);m/z (EI)410 (Mþ, 4%), 439 (M2CH3, 14),
194 (M2C12H10O3N, 27) and 178 (M2C12H10O4N, 100).
Found: Mþ 410.2229. C24H30N2O4 requires Mþ 410.2206.
1.3.1. 1-Methyl-piperidin-3-ylmethyl 2-(3-methyl-2,5-
dioxopyrrolidin-1-yl)benzoate 27. The reaction was
carried out according to the standard procedure using
1-methyl-piperidin-3-ylmethyl
2-aminobenzoate
16
(200 mg, 0.81 mmol) and methylsuccinic anhydride 28
(276 mg, 2.41 mmol) using 4:1 dichloromethane–methanol
as solvent for flash chromatography to afford the title
compound 27 (266 mg, 96%) as a clear oil. nmax (NaCl)/
cm21 2938 (C–H), 1776 (OvC–N–CvO), 1712 (CvO),
1578, 1492, 1393 and 1263; dH (400 MHz; CDCl3) 1.01–
1.04 (1H, m, 400A-H), 1.44 (3H, br d, 30-CH3), 1.58–1.80
(4H, m, 200 A-H, 400 B-H and 500 –CH2), 1.93 (1H, d,
Jgem¼10.3 Hz, 600 A-H), 2.07–2.13 (1H, br m, 300-H), 2.28
(3H, s, N-CH3), 2.43–2.56 (1H, br m, 30-H), 2.77 (1H, d,
Jgem¼10.9 Hz, 600 B-H), 2.87 (1H, d, Jgem¼10.7 Hz, 200
B-H), 3.02–3.08 (2H, br m, 40-CH2), 4.01–4.12 (2H, m,
OCH2), 7.22 (1H, d, J¼7.8 Hz, 3-H), 7.49 (1H, td,
J¼7.6 Hz, 1.4, 5-H), 7.63 (1H, td, J¼7.2 Hz, 1.8, 4-H)
and 8.08 (1H, dd, J¼1.2 Hz, 6.9, 6-H); dC (100 MHz;
CDCl3) 17.1 (CH3, 30-CH3), 25.2 (CH2, C-500), 27.2 (CH2,
C-400), 35.8 (CH, C-300), 36.4 (CH, C-30), 37.6 (CH2, C-40),
47.1 (CH3, NCH3), 56.6 (CH2, C-600), 59.5 (CH2, C-200), 68.4
(CH2, OCH2), 127.9 (quat., C-1), 129.9 (CH, C-5), 130.4
(CH, C-3), 131.1 (CH, C-6), 133.4 (quat., C-2), 133.9 (CH,
C-4), 164.9 (quat., OCvO), 176.5 (quat., C-50) and 180.5
(quat., C-20); m/z (EI) 344 (Mþ, 45%), 329 (M2CH3, 5),
1.3.4. Cyclohexyl 2-(3-methyl-2,5-dioxopyrrolidin-1-
yl)benzoate 31. The reaction was carried out according to

D. Barker et al. / Tetrahedron 60 (2004) 5953–5963
5963
Schuurmans, M.; van der Oost, J.; Smit, A. B.; Sixma, T. K.
Nature 2001, 411, 269.
the standard procedure using cyclohexyl 2-aminobenzoate
22 (100 mg, 0.456 mmol) and methylsuccinic anhydride
(156 mg, 1.37 mmol) using 1:1 hexane–ethyl acetate as
solvent for flash chromatography to afford the title
compound 31 (101 mg, 70%) as a yellow oil. nmax (NaCl)/
cm21 2937 and 2859 (C–H), 1781 (OvC–N–CvO), 1715
(CvO), 1602, 1492, 1453, 1390 and 1259; dH (200 MHz;
CDCl3) 1.25–1.94 (13H, m, 5£CH2 and 30-CH3), 2.46–2.61
(1H, m, 30-H), 3.05–3.15 (2H, m, 40-CH2), 4.85–4.94 (1H,
m, 100-H), 7.23 (1H, dd, J¼1.4 Hz, 7.8, 3-H), 7.50 (1H, td,
J¼7.5 Hz, 1.1, 5-H), 7.63 (1H, td, J¼7.6 Hz, 1.5, 4-H) and
8.10 (1H, d, J¼6.9 Hz, 6-H); dC (50 MHz; CDCl3) 16.3
(CH3, 30-CH3), 23.6 (CH2, C-300), 25.2 (CH2, C-400), 31.4
(CH2, C-200), 35.1 (CH2, C-40), 36.8 (CH, C-30), 73.4 (CH,
C-100), 126.2 (quat., C-1), 129.1 (CH, C-5), 129.5 (CH, C-3),
131.2 (CH, C-6), 131.3 (quat., C-2), 132.9 (CH, C-4), 164.3
(quat., OCvO), 175.8 (quat., C-50) and 179.7 (quat., C-20);
m/z (EI) 315 (Mþ, 2%), 216 (M2C6H11O, 100) and 188
(M2C7H11O2, 40). Found: Mþ 315.1466. C18H21NO4
requires Mþ 315.1470.
4. Paterson, D.; Nordberg, A. Prog. Neurobiol. 2000, 61, 75.
5. Davies, A. R. L.; Hardick, D. J.; Blagbrough, I. S.; Potter, B. V.
L.; Wolstenholme, A. J.; Wonnacott, S. Neuropharmacology
1999, 38, 679.
6. Marks, M. J.; Stitzel, J. A.; Romm, E.; Wehner, J. M.; Collins,
A. C. Mol. Pharmacol. 1986, 30, 427.
7. McIntosh, J. M.; Santos, A. D.; Olivera, B. M. Annu. Rev.
Biochem. 1999, 68, 59.
8. (a) Manske, R. H. Can. J. Res. 1938, 16B, 57. (b) Pelletier,
S. W.; Joshi, B. S. Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Springer: New York, 1991;
Vol. 7, p 297.
9. Hardick, D. J.; Blagbrough, I. S.; Cooper, G.; Potter, B. V. L.;
Critchley, T.; Wonnacott, S. J. Med. Chem. 1996, 39, 4860.
10. Jennings, K. R.; Brown, D. G.; Wright, P. D., Jr. Experientia
1986, 42, 611.
11. (a) Bergmeier, S. C.; Lapinsky, D. J.; Free, R. B.; McKay,
D. B. Bioorg. Med. Chem. Lett. 1999, 9, 2263. (b) Doisy, X.;
Blagbrough, I. S.; Wonnacott, S.; Potter, B. V. L. Pharm.
Pharmacol. Commun. 1998, 4, 313.
1.3.5. 1.1.1-Phenylethyl 2-(3-methyl-2,5-dioxopyrroli-
din-1-yl)benzoate 32. The reaction was carried out
according to the standard procedure using 1-phenylethyl
2-aminobenzoate 23 (70 mg, 0.29 mmol) and methyl-
succinic anhydride (132 mg, 1.16 mmol) using 1:1 hexane–
ethyl acetate as solvent for flash chromatography to afford
the title compound 32 (49 mg, 50%) as an orange oil. nmax
(NaCl)/cm21 2979, 1775 (OvC–N–CvO), 1713 (CvO),
1602, 1493, 1454, 1390 and 1259; dH (400 MHz; CDCl3)
1.24–1.39 (3H, m, 30-CH3), 1.62 (3H, d, J¼6.5 Hz, 200-
CH3), 2.37–2.43 (1H, m, 30-H), 2.86–3.04 (2H, m, 40-H),
6.01 (1H, q, J¼6.5 Hz, 100-CH), 2.23–7.40 (6H, m, 3-H and
5£Ar-H), 7.50 (1H, td, J¼7.7 Hz, 1.1, 5-H), 7.64 (1H, td,
J¼7.5 Hz, 1.5, 4-H) and 8.14 (1H, d, J¼7.5 Hz, 6-H); dC
(100 MHz; CDCl3) 16.7 (CH3, 30-CH3), 22.5 (CH3, C-200),
35.8 (CH2, C-40), 37.4 (CH, C-30), 74.1 (CH, C-100), 126.9
(quat., C-1), 128.7 (CH, Ar), 128.7 (CH, Ar), 128.9 (CH,
Ar), 129.2 (CH, C-5), 129.9 (CH, C-3), 130.2 (CH, Ar),
132.1 (CH, C-6), 132.5 (CH, Ar), 132.9 (quat., C-2), 133.8
(CH, C-4), 141.7 (quat., Ar), 164.5 (quat., OCvO), 176.3
(quat., C-50) and 180.5 (quat., C-20); m/z (EI) 337 (Mþ, 6%),
322 (M2CH3, 8) and 188 (M2C8H9O, 100). Found: Mþ
337.1313. C20H19NO4 requires Mþ 337.1314.
12. Trigg, W. J.; Hardick, D. J.; Grangier, G.; Wonnacott, S.;
Lewis, T.; Rowan, M. G.; Potter, B. V. L.; Blagbrough, I. S.
ACS Symp. Ser. 1998, 686, 194.
13. (a) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.;
Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1998, 4047.
(b) Kraus, G. A.; Dneprovskaia, E. Tetrahedron Lett. 1998, 39,
2451.
14. (a) Davies, A. R. L.; Hardick, D. J.; Blagbrough, I. S.; Potter,
B. V. L.; Wolstenholme, A. J.; Wonnacott, S. Biochem. Soc.
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Acknowledgements
Generous financial assistance from Dunlena Pty. Ltd and an
Australian Postgraduate Award (Industry) to D.B.
(C29804582) supported this work.
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