A formal synthesis of (±)-physostigmine via 3,3-rearrangement of a bis-enamine

Article abstract of DOI:10.1016/j.tet.2005.07.030

A new flexible approach to hexahydropyrrolo[2,3-b]indole system via the [3,3]-sigmatropic rearrangement of 1-(2′-methoxycarbonyl-N- methylvinylamino)skatole, culminating in the synthesis of (±)- desoxyeseroline, is described.

Full text of DOI:10.1016/j.tet.2005.07.030

Tetrahedron 61 (2005) 9147–9156
A formal synthesis of (G)-physostigmine via 3,3-rearrangement of
a bis-enamine*
Paulo F. Santos,a Natarajan Srinivasan,b Paulo S. Almeida,c Ana M. Lobob,
*
and Sundaresan Prabhakarb,
*
a
´
´
Chemistry Department, Centro de Quımica, University of Tras-os-Montes and Alto Douro, Apartado 202, 5001-911 Vila Real, Portugal
bChemistry Department, REQUIMTE/CQFB, Campus Faculty of Sciences and Technology, New University of Lisbon, and
SINTOR-UNINOVA, 2829-516 Monte de Caparica, Portugal
´
Chemistry Department, Unidade I&D de Materiais Texteis e Papeleiros, University of Beira Interior, 6201-001 Covilha˜, Portugal
c
Received 30 May 2005; accepted 11 July 2005
Available online 2 August 2005
Abstract—A new flexible approach to hexahydropyrrolo[2,3-b]indole system via the [3,3]-sigmatropic rearrangement of 1-(20-
methoxycarbonyl-N-methylvinylamino)skatole, culminating in the synthesis of (G)-desoxyeseroline, is described.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
achieved in a variety of interesting ways, still necessitated
a number of trivial, but nonetheless, obligatory functional
group transformations to construct ring C.
(K)-Physostigmine (1a) (Fig. 1), the major alkaloid of
Physostigma venenosum (Balf.) seeds (Calabar beans)2 is a
member of a class of natural products incorporating the
hexahydropyrrolo[2,3-b]indole nucleus. Some representa-
tive natural products, excluding those containing a
diketopiperazine ring,3 are (K)-debromoflustramine B
(2a),4 (K)-flustramine A (2b)5 and (K)-pseudophrynami-
nol (2c).6 (K)-Physostigmine shows wide biological
activity7 and the finding that suitably altering its carbamate
side chain, for example, 1d, afforded a derivative of much
improved pharmacological profile in the fight against
Alzheimer disease8 has stimulated, during the last decade,
studies aimed at constructing the skeleton of the alkaloid by
expeditious and novel routes.
During our studies on pericyclic reactions over a period of
years, we have reported their applications to the synthesis of
a variety of heterocycles.11 It was shown that the
rearranging system 5 (Scheme 2), generated from an
aromatic hydroxamic acid derivative 4 containing a SPh
functionality acting as an anion stabilising group,12
underwent smooth rearrangement to the substituted
o-aminophenylacetic acid derivative 6, which was sub-
sequently elaborated, via 7, to 1c.9u
It was anticipated that the aminoethyl side chain equivalent
could be directly introduced by a similar sigmatropic
process involving cleavage of the N–N bond of an
Amongst many syntheses9 of alkaloid 1a and related
substances reported to date, a number of them involve an
appropriate 1,3-dimethyloxindole (3, R2ZR3ZMe) playing
a central role10 (Scheme 1).
Introduction of the aminoethyl side chain or its synthetic
equivalent with chiral induction,9a–n or otherwise,9o–w
* Part of this work has been published as a communication, see Ref. 1.
Keywords: Physostigmine; Eseroline; Enamines; Sigmatropic
rearrangements.
*
Corresponding authors. Tel.: 351 21 2948387; fax: 351 21 2948550
(A.M.L.); e-mail addresses: aml@fct.unl.pt; sprabhakar@fct.unl.pt
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.030

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P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
Scheme 3.
of the resulting hydrazine 8 (40% yield), into the formamide
1
916 with formic acid under reflux. Its H NMR spectrum
disclosed the presence of two rotamers (1:2) with the major
isomer attributed the trans structure on the basis of the
coupling constant (JZ10.4 Hz) of the formamide protons
NH–C(O)H. LAH reduction of formamide 9 yielded 10,16
which on reaction with 2-(phenylsulfanyl)acetic acid (12) in
the presence of DCC and 4-DMAP, provided 11 in 70%
yield.
Figure 1. Molecules related to physostigmine, containing the hexahy-
dropyrrolo[2,3-b]indole nucleus.
However, all efforts to induce the desired rearrangement of
the derived enolate 13a (Scheme 4) or the corresponding
silyl ether 13b generated in situ, under a variety of
conditions, only met with failure; either the starting material
appropriate indole derivative. It was further expected that,
should such a reaction occur, the appositely generated
electrophilic and nucleophilic centres would cyclise13 to
install rings B and C in cis fusion in one step.14
The requisite starting material for the contemplated
synthesis, the phenylthioacetamide 11 (Scheme 3) was
secured by N-amination of skatole15 followed by conversion
Scheme 2.
Scheme 4.

P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
9149
Scheme 5. Reagents and conditions: (a) KHMDS (1.1 equiv), THF, K80 8C to rt, 1 h, rt, 2 h, 45 8C, 2 h, reflux, 50 h; (b) KH (1.1 equiv), THF, K80 8C to rt,
2 h, reflux 30 h; (c) KHMDS (1.1 equiv), (MeOCH2CH2)2O, 120–130 8C, 3 h (d) KHMDS (1.1 equiv), TMSCl (2.0 equiv), (MeOCH2CH2)2O, K80 8C to rt,
1 h, 120–130 8C, 32 h, reflux, 27 h.
was largely returned or a complex mixture of products
obtained.
yield (91%) was achieved when the rearrangement was
carried out in o-dichlorobenzene under reflux (35 h).
Scheme 5 summarises the results obtained under different
experimental conditions and indicates that radical processes
are most probably involved in the formation of some of the
products, especially 14 and those of type 15.
As in 19, the C8a–H in 21 resonated at d 5.05 as a singlet
indicating that ring C of hexahydropyrrolo[2,3-b]indole ring
system had been established in one step. Although in
principle the synthesis of DL-desoxyeseroline (1c) from the
tricycle 21 involved four simple steps, namely N8-
methylation, saturation of the double bond and removal of
the ester functionality, in actual practice the last step in this
sequence could not be realised. Thus, the N-methyl
It was thought that the failure of 11 to undergo a 3,3-shift
could be overcome if the relatively weak N–N bond is
further weakened by incorporation of an EWG at the
terminal position in the pendant N-vinyl group. In the event
this minor structural modification led to a successful
synthesis of (G)-desoxyeseroline (1c), which we had earlier
reported in a preliminary communication.1 Full details of
the work are described herein.
Dimethyl acetylenedicarboxylate was initially chosen for
the study. Addition of 10 to the diester in methanol at rt,
cleanly provided in a near quantitative yield a mixture of 16
(Z-isomer, 32%) and 17 (E-isomer, 63%) (Scheme 6).
Their olefinic hydrogens resonated at d 5.48 and 4.73,
respectively. The attribution of the E-geometry for the
isomer with lower d value was based on the comparison of
its chemical shift with that of similar olefinic hydrogen d
(4.60) in the 1H NMR spectra of dimethyl 2-(methylamino)
maleate.17 The olefinic mixture on thermolysis in diphenyl
ether at 180–200 8C (ca. 8 h) afforded, probably via 18, the
tricyclic compound 19 (45%) as a yellow oil. Its molecular
formula as determined by accurate mass measurement and
IR spectrum were fully consistent with the proposed
structure. More importantly, the resonance signals (1H
NMR) at d 1.67 (C3a–CH3) and d 5.12 (C8a–H) uniquely
defined its structure.
A similar addition to methyl propiolate, a less reactive
Michael acceptor, required a higher temperature and
extended reaction time (MeOH, reflux, 14 h) to give the
enaminoester 20. Thermolysis of finely ground 20 in
diphenyl ether at 210–220 8C (3 h) furnished the tricycle
21 in 51% yield (Scheme 7). Significant improvement in
Scheme 6.

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P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
vis 25b the b configuration is assigned to the latter.
Consistent with this attribution, is the observation that a
pure sample of 25b on exposure to a methanolic sodium
methoxide solution epimerises to the more stable 25a.
Selective hydrolysis of the ester group in 25a or in 25a, 25b
mixture with aqueous methanolic NaOH (1 N; 1 equiv)
followed by evaporation of the solvents gave the
corresponding salt 26a (Scheme 9), which was thoroughly
dried in high vacuum prior to use. The derived acid chloride
26b, formed in situ with oxalyl chloride, on reaction with
the anion of N-hydroxypyridine-2-thione yielded the Barton
ester 27 that on decarboxylation in the usual manner (AIBN,
TBSH)20 afforded the product 28 in poor yield (24%).
Compound 27, obtained via the mixed anhydride 26c, on
photolysis in the presence of tert-butylthiol as the hydrogen
donor21 underwent decarboxylation to afford an improved
yield of 28 (51%). A considerable improvement in this yield
(92%) was achieved on irradiating22 the benzophenone
oxime ester 29 secured in 75% yield via the mixed
anhydride 26c, in a THF–isopropanol mixture containing
a large excess of tert-butylthiol (10 mmol).
The presence of a 2H triplet centred at d 2.04 (C3–H) in
its1H NMR spectrum and a single CO absorption (IR) taken
in conjunction with the elemental analysis confirmed the
structure assigned to 28. Although LAH reduction of
N,N-disubstituted carbamates in general provides the
corresponding tertiary amines,23 such a reduction of 28
yielded N8-nordesoxyeseroline (30) (mp 110–112 8C; 69%
lit.24 111–112 8C) with d values in its 13C NMR spectrum
coincident with those reported for such compound.25
N-methylation, carried out at pHz6, with aqueous formalin
and NaBH3CN,26 furnished (G)-desoxyeseroline (1c) as a
pale yellow oil (PTLC; 67% yield). It formed a picrate, mp
183–184 8C (from EtOH), lit.10 mp 179–180 8C, and the d
Scheme 7.
compound 22 secured in 75% yield (NaH, DMF, 15-crown-
5, THF, MeI, 92%), on reduction (PtO2–H2; rt) furnished the
corresponding dihydro compound 23 of undetermined
stereochemistry in high yield.
Although the Na salt of the acid was readily formed by base
hydrolysis of the ester 23, the corresponding Barton ester
could not be obtained in any synthetically meaningful yield
via the activated carboxylic acid derivatives with the usual
coupling agents, such as isobutylchloroformate18 or (EtO)2-
P(O)CN19 and the anion of N-hyroxypyridine-2-thione.
1
values of the various hydrogens in its H NMR spectrum
were in full accordance with those reported.14b
Since (K)-desoxyeseroline (1c) had been previously
converted into (K)-eseroline (1b) and hence to (K)-
physostigmine (1a)27 this work constitutes also a formal
synthesis of (G)-physostigmine.
On the assumption that the nucleophilicity of N8 could be
responsible for the observed failure, 21 was first converted
into its methylcarbamate derivative 24 (81%) (Scheme 8).
Whilst saturation of the double bond of 24 with Pt8–H2
provided 25b (b-ester: C3a–CH3, d 1.68; C8a–H, d 5.18) as
the exclusive product (98%), the use of Pd produced a
diastereomeric mixture of 25a (a-ester: 58%: C3a–CH3, d
1.27; C8a–H, d 4.56) and 25b (35%). In view of the lower d
In summary, a novel route to 3a-methyl hexahydropyr-
rolo[2,3-b]indole nucleus involving a pericyclic reaction of
a N-aminoskatole derivative as the starting material is
described. The protocol employed above is applicable, in
principle, to the diastereoselective synthesis of alkaloids by
using chiral Michael acceptors (e.g., a chiral acetylene
sulphoxide or a chiral propiolic ester).
`
values of the C3a–CH3 and C8a–H resonances for 25a vis a
Scheme 8.

P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
9151
Scheme 9. Reagents and conditions: (a) oxalyl chloride, C6H6, reflux; (b) N-hydroxpyridine-2-thione sodium salt, reflux; (c) ClCO2CH2CH(CH3)2, THF,
K20 8C; (d) Ph2C]NOH/Et3N; (e) AIBN, nBu3SnH; (f) hn, THF, tButSH; (g) hv, Me2CHOH, THF, tBuSH; (h) LAH, THF, reflux, (69%) or aqueous NaOH
5 N MeOH, reflux, (66%); (i) aqueous formalin, NaBH3CN; pH 6.
2. Experimental
for 3 h 30 min, the reaction mixture was filtered at reduced
pressure and the filtrate evaporated to dryness. To the
residue was added Et2O and the resulting mixture again
filtered to remove the residual N,N-dicyclohexylurea. The
filtrate was then washed sequentially with 5% aqueous
NaHCO3, 5% aqueous HCl and water. The oil obtained on
usual work-up was purified by preparative TLC (silica,
CH2Cl2//n-hexane 1:1) to give, after recrystallization from
Et2O/n-hexane, 11 (3.32 g, 70%), as colourless needles: mp
2.1. General
Melting points were determined on a Reichert Thermovar
apparatus and are uncorrected. IR spectra were measured on
a Buck Scientific 500 spectrophotometer. 1H and 13C NMR
spectra were recorded on a Brucker ARX 400 spectrometer
unless otherwise stated. Chemical shifts are reported
relative to tetramethylsilane as internal reference (d 0.00)
1
75.0–75.5 8C; IR (KBr) nmax 1686 (s, C]O) cmK1; H
for H spectra and to CDCl3 (d 77.00) for 13C spectra. The
1
NMR d 7.58 (1H, d, JZ7.8 Hz, ArH), 7.36–7.14 (8H, m,
ArH), 6.73 (1H, s, NCH]C), 3.50/3.47 (2H, AB system,
JZ14.9 Hz, CH2SPh), 3.30 (3H, s, NCH3), 2.30 (3H, d, JZ
1.2 Hz, CCH3); MS (EI) m/z 310 (MC, 93.6), 160 (32.0),
159 (100.0). Anal. Calcd for C18H18N2OS: C 69.65; H 5.85;
N 9.03. Found: C 69.76; H 5.97; N 9.00.
solvent used was CDCl3, unless stated otherwise. Ordinary
mass spectra were recorded on a Fisons TRIO 2000 or AEI
MS-9 spectrometer. High resolution mass spectra were
recorded on a AutoSpecQ spectrometer. Elemental analyses
were performed by the National Institute of Engineering and
Industrial Technology, Lisbon. Thin-layer chromatography
was performed on Merck silica gel 60 F254 plates. Column
chromatography was carried out on Merck silica gel 60
(70–230 mesh). Hydrogenation reactions were carried out in
a Parr 3911 hydrogenator, at rt. Usual work up implies
drying the water or brine washed organic extracts over
anhydrous sodium sulphate or magnesium sulphate,
followed by filtration and evaporation of the solvent from
the filtrate under reduced pressure. Anhydrous solvents
were dried28 and freshly distilled.
2.2. Reaction of 11 with base
2.2.1. KHMDS in THF. To a stirred suspension of KH
(0.78 mmol, 89 mg of a 35% dispersion, washed free of
mineral oil with anhydrous THF), in anhydrous THF
(8 mL), at rt under N2 atmosphere, was added bis(trimethyl-
silyl)amine (0.15 mL, 0.71 mmol). After further stirring for
2 h, the suspension was cooled to K80 8C and a solution of
11 (200 mg, 0.65 mmol) in the same solvent (5 mL) was
added dropwise. The reaction mixture was stirred for 1 h,
while the temperature was allowed to rise slowly to rt. After
being stirred for 2 h at rt, 2 h at 45 8C and 50 h under reflux,
the reaction mixture was cooled, diluted with water,
neutralized with 5% aqueous HCl and extracted with ethyl
acetate. The combined organic layers were washed with 5%
aqueous NaHCO3 and water and dried. After removal of the
solvent at reduced pressure, the resulting brown oil was
2.1.1. 1-[N-Methyl-20-(phenylsulfanyl)acetamido]-3-
methylindole (11). To a solution of 3-methyl-1-(methyla-
mino)indole (10) (2.45 g, 15.3 mmol), 2-(phenylsulfanyl)-
acetic acid (12) (2.85 g, 16.9 mmol) and 4-DMAP (0.38 g,
3.1 mmol) in anhydrous CH2Cl2 (80 mL), under vigorous
stirring at rt, was added dropwise a solution of DCC (3.32 g,
16.1 mmol) in the same solvent (50 mL). After being stirred

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P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
subjected to preparative TLC (silica, Et2O/n-hexane 1:1) to
give, in increasing order of polarity: bis(phenylsulfanyl)-
methane (14) (6 mg, 4%), as a yellow solid: mp 33–37 8C
(from n-hexane) (lit.29 mp 36–38 8C); IR (film) nmax 1588,
(15c) (16 mg, 12%), as a colourless solid: mp 140–141 8C,
after recrystallization form Et2O/n-hexane (lit.30 mp 140.5–
1
141.0 8C); IR (KBr) nmax 1684 (C]O) cmK1; H NMR d
7.60 (1H, d, JZ7.8 Hz, ArH), 7.31–7.18 (3H, m, ArH), 6.84
(1H, s, NCH]C), 3.33 (3H, s, NCH3), 2.33 (3H, JZ1.0 Hz,
CCH3), 1.85 (3H, s, COCH3); MS (EI) m/z 202 (MC, 100.0).
From the aqueous NaHCO3 extracts was isolated, as in
procedure (a), 2-(phenylsulfanyl)acetic acid (12) (17 mg,
16%), as a colourless solid, which was identical with an
authentic sample.
1
1484, 1442, 1268, 1204, 1092, 1028, 744 cmK1; H NMR
(acetone-d6) d 7.47–7.44 (4H, m, ArH), 7.37–7.33 (4H, m,
ArH), 7.29–7.25 (2H, m, ArH), 4.56 (2H, s, CH2); MS (EI)
m/z 232 (MC, 74.3), 123 (85.3), 109 (13.8), 51 (38.5), 45
(100.0); and recovered 11 (74 mg, 37%). From the original
base extract 2-(phenylsulfanyl)acetic acid (12) was obtained
(after neutralisation with 5% aqueous HCl) in 17% yield
(19 mg).
2.2.4. KHMDS and TMSCl in bis(2-methoxyethyl) ether.
To a stirred suspension of KHMDS (0.71 mmol) in
anhydrous bis(2-methoxyethyl) ether (8 mL), prepared as
described above, cooled to K80 8C, under N2 atmosphere,
were added a solution of 11 (199 mg, 0.64 mmol) in the
same solvent (5 mL) and TMSCl (0.16 mL, 1.25 mmol).
The reaction mixture was stirred for 1 h, while the
temperature was left to rise slowly to rt. After being stirred
for 1 h at rt, 32 h at 120–130 8C and 27 h under reflux, the
reaction mixture was cooled, neutralized with 5% aqueous
HCl and the organic layer, separated by decantation, washed
with water and dried. Removal of the solvent at reduced
pressure and purification of the resulting residue by
preparative TLC (silica, Et2O/n-hexane 1:1), furnished 11
(157 mg, 77%).
2.2.2. KH in THF. To a stirred suspension of KH
(0.76 mmol, 87 mg of a 35% dispersion, washed free of
mineral oil with anhydrous THF) in anhydrous THF (8 mL),
cooled to K80 8C, under N2 atmosphere, was added
dropwise a solution of 11 (202 mg, 0.65 mmol) in the
same solvent (5 mL). The reaction mixture was stirred for
2 h, while the temperature was left to rise slowly to rt. After
being stirred for 2 h at rt and 30 h under reflux, the reaction
mixture was worked-up as above. Evaporation of the
combined ethyl acetate extracts, left an oil, which was
subjected to preparative TLC (silica, Et2O/n-hexane 1:1) to
give, 14 (21 mg, 28%), as a pale-yellow solid, which was
identical with a sample previously isolated; recovered 11
(36 mg, 18%), 3-methyl-1-(N-methylformamido)indole
(15a) (6 mg, 5%), as a white solid: mp 83–85 8C, on
recrystallization from Et2O/n-hexane; IR (KBr) nmax 1692
(f, C]O) cmK1; 1H NMR d 8.42 (1H, s, CHO), 7.60 (1H, d,
JZ8.1 Hz, ArH), 7.3–7.20 (3H, m, ArH), 6.88 (1H, s,
NCH]C), 3.29 (3H, s, NCH3), 2.32 (3H, s, CCH3); MS (EI)
m/z 188 (MC, 91.3), 159 (45.0), 130 (100.0); exact mass
calcd for C11H12N2O: 188.094963. Found: 188.095597; and
3-methyl-1-(methylamino)indole (10) (6 mg, 6%), as a
2.2.5. 1-[10,20-Bis(methoxycarbonyl)-N-methylvinyla-
mino]-3-methylindole (16,17). To a stirred solution of
3-methyl-1-(methylamino)indole (10) (117 mg, 0.73 mmol)
in MeOH (8 mL), at rt, was added dropwise dimethyl
acetylenedicarboxylate (0.1 mL, 0.82 mmol). After being
stirred for 3 h 10 min, the reaction mixture was evaporated
to dryness and the resulting residue subjected to preparative
TLC (silica, CH2Cl2), to give two isomers: Z isomer 16
(71 mg, 32%), as a yellow solid: mp 89.5–90.5 8C, after
recrystallization from Et2O/n-hexane; IR (KBr) nmax 1732
yellowish oil: IR (film) nmax 3310 (br, NH) cmK1 1H
;
NMR d 7.54 (1H, d, JZ7.6 Hz, ArH), 7.39 (1H, d, JZ
7.6 Hz, ArH), 7.21 (1H, t, JZ7.6 Hz, ArH), 7.10 (1H, t, JZ
7.6 Hz, ArH), 6.96 (1H, s, NCH]C), 4.23 (1H, br s, NH,
D2O exchangeable), 2.92 (3H, s, NCH3), 2.30 (3H, d, JZ
1.0 Hz, CCH3); MS (EI) m/z 160 (MC, 100.0). From the
aqueous NaHCO3 extracts was isolated 2-(phenylsulfany-
l)acetic acid (12) (16 mg, 15%).
1
(s, C]O), 1708 (s, C]O) cmK1; H NMR d 7.50 (1H, d,
JZ7.5 Hz, ArH), 7.45 (1H, d, JZ7.5 Hz, ArH), 7.25 (1H, t,
JZ7.5 Hz, ArH), 7.14 (1H, t, JZ7.5 Hz, ArH), 6.99 (1H, s,
NCH]C), 5.48 (1H, s, NC]CH), 3.76 (3H, s, OCH3), 3.55
(3H, s, OCH3), 3.29 (3H, s, NCH3), 2.27 (3H, d, JZ0.8 Hz,
CCH3); MS (EI) m/z 302 (MC, 100.0). Anal. Calcd for
C16H18N2O4: C 63.55; H 6.00; N.9.27. Found: C 63.78; H
6.14; N 9.29; E isomer 17 (139 mg, 63%), as a colourless
solid: mp 93.0–94.5 8C, after recrystallization from Et2O/n-
2.2.3. KHMDS in bis(2-methoxyethyl) ether. To a
suspension of KHMDS (0.71 mmol) in anhydrous bis(2-
methoxyethyl) ether (8 mL), prepared as previously
described, stirred at rt under N2 atmosphere, was added
dropwise a solution of 11 (200 mg, 0.65 mmol) in the same
solvent (5 mL). After the addition was complete, the
reaction mixture was heated at 120–130 8C for 3 h and
then worked-up as in procedure (a). Removal of the solvent
from the ethyl acetate extracts left an oil, which was
purified by preparative TLC (silica, Et2O/n-hexane 1:1) to
give, 1-[bis(20-phenylsulfanyl)-N-methylacetamido]-3-
methylindole (15b) (20 mg, 15%), as a yellowish oil: IR
hexane; IR (KBr) nmax 1744 (s, C]O), 1704 (s, C]O) cmK1
;
1H NMR d 7.53 (1H, d, JZ7.8 Hz, ArH), 7.29–7.15 (3H, m,
ArH), 6.84 (1H, s, NCH]C), 4.73 (1H, br s, NC]CH),
3.71 (3H, br s, OCH3), 3.64 (3H, s, OCH3), 3.16 (3H, s,
NCH3), 2.27 (3H, d, JZ0.7 Hz, CCH3); MS (EI) m/z 302
(MC, 100.0). Anal. Calcd for C16H18N2O4: C 63.55; H 6.00;
N 9.27. Found: C 64.05; H 6.11; N 9.35.
2.2.6. 2,3-Bis(methoxycarbonyl)-1,3a-dimethyl-1,3a,8,
8a-tetrahydropyrrolo[2,3-b]indole (19). A solution con-
taining the two isomers 16 and 17 (1/1.8 mixture, 322 mg,
0,11 mmol) in diphenyl ether (15 mL) was heated at 180–
200 8C in an oil bath, for 7 h 45 min. The solvent was
removed at reduced pressure and the resulting dark residue
purified by preparative TLC (silica, CH2Cl2/n-hexane 2:1)
to give 19 (145 mg, 45%), as a yellowish oil: IR (KBr) nmax
3365 (br, NH), 1748 (s, 2-COOMe), 1684 (s, 3-COOMe)
1
(film) nmax 1692 (C]O) cmK1; H NMR (acetone-d6) d
7.54 (1H, d, JZ7.5 Hz, ArH), 7.40–7.14 (10H, m, ArH),
7.09–7.03 (3H, m, ArH), 6.56 (1H, s, NCH]C), 4.50 (1H, s,
COCH), 3.31 (3H, s, NCH3), 2.15 (3H, d, JZ0.8 Hz,
CCH3); MS (EI) m/z 418 (MC, 38.5), 309 (100.0); exact
mass calcdfor C24H22N2OS2: 418.117357. Found: 418.116225;
10 (18 mg, 17%), 3-methyl-1-(N-methylacetamido)indole

P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
9153
cmK1; 1H NMR d 7.56 (1H, d, JZ7.6 Hz, ArH), 7.05 (1H, t,
JZ7.6 Hz, ArH), 6.80 (1H, t, JZ7.6 Hz, ArH), 6.68 (1H, d,
JZ7.6 Hz, ArH), 5.12 (1H, s, NCHN), 4.46 (1H, br s, NH,
D2O exchangeable), 3.88 (3H, s, OCH3), 3.69 (3H, s, OCH3),
2.83 (3H, s, NCH3), 1.67 (3H, s, CCH3); MS (EI) m/z 302
(MC, 100.0); exact mass calcd for C16H18N2O4: 302.126657.
Found: 302.125918.
exact mass calcd for C15H18N2O2: 258.12682. Found:
258.13674.
2.2.10. 3-Methoxycarbonyl-1,3a,8-trimethyl-2,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (23). Compound 22
(264 mg, 1.02 mmol) in MeOH (10 mL), was hydrogenated
in the presence of PtO2 (26 mg) at 25 psi (8 h). After
removal of the catalyst by filtration, the solvent was
evaporated at reduced pressure and the resulting residue
purified by column chromatography (EtOAc/n-hexane 1:4)
to give the title compound 23 (255 mg; 96%) as a colourless
2.2.7. 1-(20-Methoxycarbonyl-N-methylvinylamino)-3-
methylindole (20). Methyl propiolate (1.5 mL,
16.86 mmol) was added to a solution of 3-methyl-1-
(methylamino)indole (10) (0.75 g, 4.69 mmol) in MeOH
(20 mL), at rt. The reaction mixture was heated under reflux
for 14 h and then evaporated to dryness at reduced pressure
to give 20 (1.08 g, 94%), as colourless needles: mp 112.0–
112.5 8C, after recrystallization from Et2O/n-hexane; IR
solid, mp 48–50 8C; IR (KBr) nmax 1743 (s, C]O) cmK1
;
1H NMR d 7.14 (1H, t, JZ8.0 Hz/br s, ArH), 6.86 (1H, d,
JZ8.0 Hz, ArH), 6.62 (1H, t, JZ8.0 Hz, ArH), 6.44 (1H, d,
JZ8.0 Hz, Ar-H), 4.33 (1H, br s, NCHN), 3.54(3H, s, OCH3),
2.90 (3H, s, NCH3), 2.55 (3H, s, NCH3), 1.65 (3H, s, CCH3);
exact mass calcd for C15H20N2O2: 260.15247. Found:
260.15228.
1
(KBr) nmax 1698 (s, C]O) cmK1; H NMR d 7.65 (1H, d,
JZ13.2 Hz, NCH]CH), 7.57 (1H, d, JZ7.8 Hz, ArH),
7.26–7.15 (3H, m, ArH), 6.86 (1H, s, NCH]CMe), 4.61
(1H, br d, JZ13.2 Hz, NCH]CH), 3.64 (3H, s, OCH3),
3.31 (3H, s, NCH3), 2.30 (3H, d, JZ0.8 Hz, CCH3); MS
(EI) m/z 244 (MC, 100.0). Anal. Calcd for C14H16N2O2: C
68.82, H 6.61, N 11.47. Found C 68.96, H 6.66, N 11.48.
2.2.11. 3,8-Bis(methoxycarbonyl)-1,3a-dimethyl-1,3a,8,
8a-tetrahydropyrrolo[2,3-b]indole (24). A solution of
methyl chloroformate (0.09 mL, 1.16 mmol) in anhydrous
Et2O (2 mL) was added dropwise to an ice-cooled solution
of 21 (283 mg, 1.16 mmol) and 4-DMAP (142 mg,
1.16 mmol), in the same solvent (10 mL). The mixture
was stirred at rt for 2 h 30 m and then washed with water and
dried. The solvent was evaporated at reduced pressure and
the residue purified by preparative TLC (Et2O/n-hexane 2:1)
to give 24 (284 mg, 81%), as a white solid: mp 180.0–
180.5 8C, after recrystallization from acetone/Et2O; IR
2.2.8. 3-Methoxycarbonyl-1,3a-dimethyl-1,3a,8,8a-tetra-
hydropyrrolo[2,3-b]indole (21). To diphenyl ether (8 mL)
at 210–220 8C was added finely powdered 20 (625 mg,
2.56 mmol) and the mixture while being stirred was kept at
that temperature, for 2 h 50 min. The solvent was then
removed at reduced pressure and the dark residue subjected
to column chromatography (Et2O/n-hexane 1:1) to give 21
(319 mg, 51%), as a yellowish oil: IR (film) nmax 3355 (br,
(KBr) nmax 1722 (s, NCOOMe), 1678 (s, 3-COOMe) cmK1
;
1H NMR d 7.74–750 (2H, d, JZ7.5 Hz/br s, ArH), 7.20 (1H, t,
JZ7.5 Hz, ArH), 7.03 (1H, t, JZ7.5 Hz, ArH), 6.99 (1H, s,
NCH]C), 5.66 (1H, br s, NCHN), 3.90 (3H, s, OCH3), 3.68
(3H, s, OCH3), 3.02 (3H, s, NCH3), 1.70 (3H, s, CCH3); MS
(EI) m/z 302 (MC, 100.0). Anal. Calcd for C16H18N2O4: C
63.55, H 6.00, N 9.27. Found: C 63.56, H 5.97, N 9.21.
1
NH), 1674 (s, C]O) cmK1; H NMR d 7.62 (1H, d, JZ
7.5 Hz, ArH), 7.05–7.01 (2H, m, ArH and NCH]C), 6.79
(1H, t, JZ7.5 Hz, ArH), 6.67 (1H, d, JZ7.5 Hz, ArH), 5.05
(1H, s, NCHN), 4.48 (1H, br s, NH, D2O exchangeable),
3.66 (3H, s, OCH3), 2.90 (3H, s, NCH3), 1.65 (3H, s, CCH3);
MS (EI) m/z 244 (MC, 100.0); exact mass calcd for
C14H16N2O2: 244.121178. Found: 244.121673.
2.2.12. 3,8-Bis(methoxycarbonyl)-1,3a-dimethyl-1,2,3,
3a,8,8a-hexahydropyrrolo[2,3-b]indole (25aD25b). A
solution of 24 (583 mg, 1.93 mmol) in MeOH (180 mL),
containing 10% palladium on carbon (179 mg, 0.17 mmol),
was shaken under hydrogen pressure (45 Psi) for 16 h. After
removal of the catalyst by filtration over Celite, the solvent
was evaporated at reduced pressure and the residue
subjected to preparative TLC (Et2O/n-hexane 2:1) to give
the less polar diastereoisomer 25a (340 mg, 58%), as a
colourless solid: mp 154.0–154.5 8C, after recrystallization
from n-hexane; IR (KBr) nmax 1740 (s, 3-COOMe), 1712 (s,
Compound 20 (1.61 g, 6.6 mmol) in o-dichlorobenzene
(distilled, 30 mL) was heated under reflux in an argon
atmosphere (35 h). Evaporation of the solvent under
reduced pressure followed by chromatographic purification
of the resulting residue (EtOAc/n-hexane 3:7) furnished 21
(1.47 g, 91%) as a colourless solid mp 120–122 8C, identical
in all respects with the sample above.
1
2.2.9. 3-Methoxycarbonyl-1,3a,8-trimethyl-1,3a,8,8a-tet-
rahydropyrrolo[2,3-b]indole (22). Compound 21 (240 mg,
0.98 mmol) in anhydrous dichloromethane (15 mL) con-
taining 15-crown-5-ether (2 mg) and NaH (80%; 87 mg,
3 mmol) was treated with an excess of MeI (5 mmol) and
the mixture heated under reflux (15 h). Evaporation of the
solvent followed by purification of the resulting residue by
column chromatography (EtOAc/n-hexane 1:6) gave the
N-alkylated product 22 (190 mg, 75%) as a colourless solid,
mp 52–53 8C; IR (KBr) nmax 1722, 1671 cmK1; 1H NMR d
7.58 (1H, d, JZ8.0 Hz, ArH), 7.08 (2H, m, Ar-H and
NCH]C), 6.73 (1H, t, JZ8.0 Hz, Ar-H), 6.47 (1H, d, JZ
8.0 Hz, ArH), 4.71 (1H, s, NCHN), 3.65 (3H, s, OCH3), 3.02
(3H, s, NCH3), 3.00 (3H, s, NCH3), 1.63 (3H, s, CCH3);
NCOOMe) cmK1; H NMR d 7.66 (1H, br s, ArH), 7.37
(1H, d, JZ7.6 Hz, ArH), 7.23 (1H, t, JZ7.6 Hz, ArH), 7.06
(1H, t, JZ7.6 Hz, ArH), 4.56 (1H, br s, NCHN), 3.87 (3H, s,
OCH3), 3.82 (3H, s, OCH3), 3.23–3.18 (1H, m, NCH2CH),
3.08–3.04 (1H, m, NCH2CH), 2.94 (1H, t, JZ9.8 Hz,
NCH2CH), 2.59 (3H, br s, NCH3), 1.27 (3H, s, CCH3); MS
(EI) m/z 304 (MC, 32.9), 273 (8.2), 245 (7.3), 189 (50.7),
158 (23.4), 144 (14.2), 130 (23.4), 115 (100.0). Anal. Calcd
for C16H20N2O4: C 63.13; H 6.63; N 9.21. Found: C 63.07;
H 6.33; N 9.22; and the more polar diastereoisomer 25b
(205 mg, 35%), as a colourless solid: mp 73.5–75.0 8C, after
recrystallization from acetone/Et2O; IR (KBr) nmax 1734 (s,
1
3-COOMe), 1720 (s, NCOOMe) cmK1; H NMR d 7.70
(1H, br s, ArH), 7.24–7.20 (1H, m, ArH), 6.98–6.94 (2H, m,

9154
P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
ArH), 5.18 (1H, s, NCHN), 3.86 (3H, s, OCH3), 3.65 (3H, s,
OCH3), 3.20–3.16 (1H, m, NCH2CH), 2.90–2.82 (2H, m,
NCH2CH and NCH2CH), 2.56 (3H, s, NCH3), 1.68 (3H, s,
CCH3); MS (EI) m/z 304 (MC, 27.4), 273 (14.6), 245 (7.8),
189 (81.3), 158 (25.1), 144 (34.7), 130 (19.1), 115 (100.0).
Anal. Calcd for C16H20N2O4: C 63.13; H 6.63; N 9.21.
Found: C 63.23; H 6.70; N 9.21.
subjected to preparative TLC (Et2O/n-hexane 1:1) to afford
28 (196 mg, 51%), identical with that obtained by Method a.
Method c. Via oxime ester 29. To a mixture of sodium salts
26a (64 mg, 0.21 mmol) in DMF (3 mL) containing a
catalytic amount of 15-crown-5-ether cooled to 0 8C, was
added with stirring freshly distilled isobutyl chloroformate
(0.026 mL, 0.20 mmol) under N2 atmosphere. After stirring
for 1 h, the mixture was treated with benzophenone oxime
(38 mg, 0.2 mmole) and Et3N (0.12 mL, 0.6 mmol) and the
reaction allowed to stand at rt overnight. It was then diluted
with EtOAc (25 mL) and washed with water. Usual work up
led to a solid residue which was purified by preparative TLC
(EtOAc/n-hexane 1:1) to afford the oxime ester 29 as a pale
yellow solid (72 mg, 75%), mp 38–40 8C; IR (KBr) nmax
1766 (s, C]O), 1711 (NCOOMe) cmK1; 1H NMR d 7.66–
7.36 (11H, m, ArH), 7.15 (1H, t, JZ7.6 Hz, ArH), 6.77 (1H,
t, JZ7.6 Hz, ArH), 6.43 (1H, d, JZ7.6 Hz, ArH), 4.44 (1H,
s, NCHN), 3.84 (3H, s, OCH3), 3.14 (1H, d, JZ10.2,
6.6 Hz, NCH2CH), 3.04 (1H, d, JZ9.4, 6.6 Hz), 2.95 (1H, t,
CHCOO, JZ10 Hz), 2.52 (3H, s, NCH3), 1.21 (3H, s,
CCH3). exact mass calcd for C28H27N3O4: 469.20014 46.
Found 469.2002452.
The diastereomer 25b, obtained as the exclusive product
with Pt8 as the hydrogenating catalyst in anhydrous MeOH,
was found to isomerise to 25a on exposure to 1 N
methanolic sodium methoxide.
2.3. Sodium salt of 8-methoxycarbonyl-1,3a-dimethyl-1,
2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-3-carboxylic
acid (26a)
To a mixture of the diastereoisomers 25a and 25b (144 mg,
0.47 mmol) in MeOH (6 mL), was added 1 N aqueous
NaOH (0.48 mL, 0.48 mmol) and the mixture heated under
reflux for 5 h. The solvents were removed at reduced
pressure, benzene was added to the residue and the resulting
mixture evaporated to dryness at reduced pressure. The
process was repeated several times. The resulting solid,
presumably a mixture of the sodium salts 26a was dried over
phosphorous pentoxide in vacuo.
The above oxime-ester 29 (50 mg, 1.07 mmol) and t-BuSH
(0.2 mL,10 mmol) in a mixture of iso-propanol/THF (2:1,
3 mL) was irradiated (Philips HPR 125 W HG) at 25 8C for
20 h. Evaporation of solvents and excess reagent under
reduced pressure gave a residue, which was taken up in
EtOAc and washed with ice-cold 1 N aqueous NaOH and
then with water and dried (Na2SO4). The yellow solid
obtained on removal of the solvent and after purification by
column chromatography (EtOAc/n-hexane 1:50) gave 28
(23 mg, 92%) identical with that obtained by Method a.
2.3.1. 8-Methoxycarbonyl-1,3a-dimethyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole (28). Method a. A suspen-
sion of the above sodium salts 26a (49.9 mg, 0.16 mmol) in
benzene was treated with oxalyl chloride (0.015 mL,
0.18 mmol) in benzene (3 mL) and the mixture refluxed
(2 h). Subsequent to the addition of the sodium salt of
N-hydroxythiopyridine-2-thione (28.6 mg, 0.19 mmol) to
the above mixture at rt, reflux was continued for 30 min. To
the resulting yellow solution, under reflux, was added a
mixture of AIBN (4 mg, 0.024 mmol) and n-Bu3SnH
(0.13 mL, 0.48 mmol) in benzene (2 mL). On completion
of the reaction (1 h 30 m), the mixture was taken to dryness
and the residue obtained was purified by preparative TLC
(Et2O/n-hexane 1:1) to give 28 as an oil (9.4 mg, 24%); IR
(film) nmax 1712 (s, C]O) cmK1; 1H NMR d 7.66 (1H, br s,
ArH), 7.19 (1H, t, JZ7.3 Hz, ArH), 7.12 (1H, d, JZ7.3 Hz,
ArH), 7.02 (1H, t, JZ7.3 Hz, ArH), 4.89 (1H, s, NCHN),
3.86 (3H, s, OCH3), 2.71–2.60 (2H, m, NCH2CH2), 2.56
(3H, s, NCH3), 2.04 (2H, t, JZ6.2 Hz, NCH2CH2), 1.43
(3H, s, CCH3); MS (EI) m/z 246 (MC, 100.0). exact mass
calcd for C14H18N2O2: 246.136828. Found 246.136829.
2.3.2. 1,3a-Dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,
3-b]indole [(G)-N8-nordesoxyeseroline] (30). By
reduction of 28. To a solution of 28 (53.0 mg, 0.22 mmol)
in anhydrous THF (8 mL) was added LiAlH4 (15.1 mg,
0.40 mmol) and the resulting suspension heated under reflux
for 50 min. The reaction mixture was cooled in an ice-bath
and 5 N aqueous NaOH was added. The mixture was heated
under reflux for 1 h, extracted with boiling AcOEt and the
combined organic layers were dried and concentrated under
reduced pressure. Purification of the resulting residue by
preparative TLC (AcOEt/MeOH 20/1) afforded 30
(28.1 mg, 69%), as a colourless solid: mp 110–112 8C
(lit.24 mp 111–112 8C), after recrystallization from n-
hexane; IR (KBr) nmax 3180 (br, NH), 1620 cmK1 1H
;
Method b. To a mixture of sodium salts 26a (488 mg,
1.56 mmol) in anhydrous THF (6 mL), cooled to K20 8C
and under N2 atmosphere, was added isobutyl chlorofor-
mate (0.2 mL, 1.56 mmol). After stirring for 2 h, finely
powdered sodium salt of N-hydroxypyridine-2-thione
(280 mg, 1.88 mmol) was added and the suspension stirred
at K20 8C, sheltered from light, for 1 h 30 min. The
resulting yellow mixture was irradiated in the presence of
tert-butylthiol (1 mL) with a 125 W high-pressure mercury
lamp at rt, under N2 atmosphere, until the yellow color
disappeared (2 h). The reaction mixture was then diluted
with Et2O and washed sequentially with 0.1 N aqueous
NaHCO3, water and brine. The organic phase was dried, the
solvent removed at reduced pressure and the residue
NMR d 7.05–6.99 (2H, m, ArH), 6.73 (1H, t, JZ7.6 Hz,
ArH), 6.58 (1H, d, JZ7.6 Hz, ArH), 4.36 (1H, s, NCHN),
4.18 (1H, br s, NH, D2O exchangeable), 2.71–2.60 (2H, m,
NCH2CH2), 2.45 (3H, s, NCH3), 2.01–1.98 (2H, m,
NCH2CH2), 1.45 (3H, s, CCH3); 13C NMR d 149.5 (C-7a),
137.0 (C-3b), 127.5 (C-6), 122.8 (C-4), 118.8 (C-5), 109.0
(C-7), 89.7 (C-8a), 53.5 (C-3a), 52.5 (C-2), 40.9 (C-3), 37.0
(1-CH3), 27.0 (3a-CH3); MS (FAB, glycerol) m/z 189 ([MC
H]C, 100.0).
By hydrolysis of 28. To a solution of 28 (31.0 mg,
0.13 mmol) in MeOH (3 mL) was added 5 N aqueous
NaOH (0.1 mL, 0.5 mmol) and the resulting suspension
heated under reflux for 3 h. The reaction mixture was

P. F. Santos et al. / Tetrahedron 61 (2005) 9147–9156
9155
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York, 1999; Vol. 13, pp 163–236.
cooled, diluted with water and extracted with Et2O. The
combined organic layers were washed with brine and dried.
After removal of the solvent at reduced pressure, the
resulting residue was subjected to preparative TLC (AcOEt/
MeOH 20/1) to give 30 (15.7 mg, 66%), which was identical
with a sample prepared by method a.
3. (a) Amauromine: Takase, T.; Iwami, M.; Aoki, M.; Imanaka,
H. J. Antibiot. 1984, 37, 1320–1323. (b) 5-N-Acetylardeemin:
Hochlowski, J. P.; Jackson, M.; Rasmussen, R. R.; Humphrey,
P. E.; Poddig, J. B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.;
McAlpine, J. B. J. Antibiot. 1993, 46, 374–379. (c)
Aszonalenin: Kimura, Y.; Hamasaki, T.; Nakagima, H.;
Isogai, A. Tetrahedron Lett. 1982, 23, 225–228. (d)
Roquefortine: Scott, P. M.; Merrien, M.-A.; Polonsky, J.
Experientia 1976, 32, 140–142. These are a few examples of
natural products that are characterised by the presence of
diketopiperazine ring built on a hexahydropyrrolo[2,3-b]
indole nucleus.
2.3.3. 1,3a,8-Trimethyl-1,2,3,3a,8,8a-hexahydro-pyr-
rolo[2,3-b]indole [(G)-desoxyeseroline] (1c). To an ice-
cooled solution of 30 (13.5 mg, 0.07 mmol) in MeOH
(3 mL) was added NaBH3CN (9.1 mg, 0.14 mmol). The
mixture was then adjusted to pHz6 with 1% aqueous HCl
and 35% aqueous formalin (2.1 mL, 24.5 mmol) added.
After being stirred at rt for 1 h 10 min, the reaction mixture
was evaporated to dryness under reduced pressure and the
residue basified with 25% aqueous NH4OH. The resulting
mixture was extracted with AcOEt, the combined organic
extracts washed with brine, dried and the solvent removed
under reduced pressure. Purification of the residue by
preparative TLC (alumina, Et2O/n-hexane 1.5:9), afforded
1c (9.7 mg, 67%), as a yellowish oil: IR (film) nmax 1605,
1495, 1450, 1345, 1300, 1255, 1120, 1035, 1020, 955,
4. Holst, B.; Anthoni, U.; Christophersen, C.; Nielson, P. H.
J. Nat. Prod. 1994, 57, 997–1000.
´
5. Carle, J. S.; Christophersen, C. J. Am. Chem. Soc. 1980, 45,
1586–1589.
6. Spande, F.; Edwards, M. W.; Pannel, L. K.; Daly, J. W.;
Erspamer, V.; Melchiorri, P. J. J. Org. Chem. 1988, 53,
1222–1226.
1
735 cmK1; H NMR (300 MHz) d 7.08 (1H, td, JZ1.1,
7. For recent reviews on pharmacological properties, see: (a)
Brossi, A. J. Med. Chem. 1990, 33, 2311–2319. (b) Greig,
N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A.
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7.5 Hz, ArH), 7.00 (1H, d, JZ1.1, 7.5 Hz, ArH), 6.68 (1H,
dt, JZ1.1, 7.5 Hz, ArH), 6.42 (1H, d, JZ7.5 Hz, ArH), 4.12
(1H, s, NCHN), 2.95 (3H, s, NCH3), 2.77–2.59 (2H, m,
NCH2CH2), 2.55 (3H, s, NCH3), 1.99–1.95 (2H, m,
NCH2CH2), 1.44 (3H, s, CCH3); 13C NMR (75 MHz) d
151.9, 136.6, 127.7, 122.2, 117.5, 106.6, 97.5 (C-8a), 53.2
(C-2), 52.7 (C-3a), 40.8 (C-3), 38.4 (8-CH3), 36.5 (1-CH3),
27.3 (3a-CH3); MS (EI) m/z 202 (MC, 100.0); exact mass
calcd for C13H18N2: 202.146999. Found: 202.147656.
8. For efforts against Alzheimer disease, see: Brossi, A.; Pei, X.-
F.; Greig, N. H. Aust. J. Chem. 1996, 49, 171–181 and
references therein.
9. Chiral syntheses: (a) Lee, B. K.; Wong, G. S. K. J. Org. Chem.
1991, 56, 872–875. (b) Ashimori, A.; Matsuura, T.; Overman,
L. E. J. Org. Chem. 1993, 58, 6949–6951. (c) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6500–6503. (d) Huang, A.; Kodanko, A.; Overman, L. E.
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Luo, W.-M.; Li, Y.-Q.; Brossi, A. Heterocycles 1993, 36,
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Ogasawara, K. Chem. Lett. 1990, 109–112. (g) Node, M.;
Hao, X.; Fuji, K. Chem. Lett. 1991, 57–60. (h) Pallavicini, M.;
Valoti, E.; Villa, L.; Resta, I. Tetrahedron: Asymmetry 1994, 5,
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Chem. Soc. 1992, 114, 5566–5572. (j) Takano, S.; Moriya, M.;
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The picrate of 1c, obtained as yellow crystals, had: mp
182.5–184 8C (lit.10 mp 179–180 8C), on recrystallization
from EtOH; IR (KBr) nmax 1635, 1615, 1565 (s, NO2), 1490,
1430, 1360, 1320 (s, NO2), 1275, 1165, 1075, 1005, 910,
1
785, 740 cmK1; H NMR (300 MHz) d 11.30 (1H, br s,
NH), 8.93 (2H, s, ArH), 7.24 (1H, t, JZ7.2 Hz, ArH), 7.11
(1H, d, JZ7.2 Hz, ArH), 6.92 (1H, t, JZ7.2 Hz, ArH), 6.66
(1H, d, JZ7.2 Hz, ArH), 5.16 (1H, d, JZ3.0 Hz,
NCHN),3.71–3.65 (1H, m, NCH2CH2), 3.19 (3H, s,
NCH3), 2.83 (3H, d, JZ4.5 Hz, NCH3), 2.71–2.61 (1H,
m, NCH2CH2), 2.57–2.47 (1H, m, NCH2CH2), 2.35–2.30
(1H, m, NCH2CH2), 1.55 (3H, s, CCH3).
Acknowledgements
ˆ
We are grateful to Fundac¸a˜o para a Ciencia e a Tecnologia
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X.-F.; Bi, S. Heterocycles 1994, 39, 357–360. (r) Ishibashi, H.;
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(FC&T, Lisbon, Portugal) for partial financial support.
Three of us (P. F. S., N. S. and P. S. A.) also thank FC&T for
the award of research fellowships.
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