A formal synthesis of (±)-eseroline via an azaoxy-cope rearrangement

Article abstract of DOI:10.3987/com-01-9177

A novel synthesis of (±)-desoxyeseroline, from the crucial oxindole (15), obtained by a 3,3-sigmatropic rearrangement of the enolate derived from the hydroxamic acid derivative (5) followed by radical desulfurisation, has been described. The requisite C

Full text of DOI:10.3987/com-01-9177

HETEROCYCLES, Vol. 55, No. 6, 2001, pp. 1029 - 1043, Received, 9th February, 2001
A FORMAL SYNTHESIS OF (±)-ESEROLINE VIA AN AZAOXY-COPE
†
REARRANGEMENT
a
Paulo F. Santos, Paulo S. Almeida, Ana M. Lobo,
b
,c,‡
*
and Sundaresan
,c,‡
*
Prabhakar
a
Chemistry Department, University of Trás-os-Montes and Alto Douro, Apartado
202, 5001-911 Vila Real, Portugal
b
Chemistry Department, University of Beira Interior, 6200-053 Covilhã, Portugal
c
Chemistry Department, Center for Fine Chemistry and Biotechnology, Faculty of
Sciences and Technology, New University of Lisbon, and SINTOR-UNINOVA, 2825-
114 Monte de Caparica, Portugal
Abstract - A novel synthesis of (±)-desoxyeseroline, from the crucial oxindole (15),
obtained by a 3,3-sigmatropic rearrangement of the enolate derived from the
hydroxamic acid derivative (5) followed by radical desulfurisation, has been
described. The requisite C N fragment has been introduced through a Michael
2
addition of nitroethylene to 15.
1
(-)-Physostigmine (1), the major alkaloid of Physostigma venenosum (Balf.) seeds (Calabar beans), is a
2
highly potent acetylcholinesterase inhibitor and has been used medically in the treatment of glaucoma,
3
4
myasthenia gravis and as an antidote against organophosphorous poisoning. More recently the
5
therapeutic properties shown by physostigmine (1) towards Alzheimer's disease and the improved
6
pharmacological activity exhibited by some analogues bearing different carbamate side chains have
prompted a renewed interest in the alkaloid. Furthermore (-)-eseroline (2), a major metabolite of (-)-
7
physostigmine (1), is known to possess an analgesic effect similar to that of morphine. As a consequence
many syntheses, chiral or otherwise, of this class of compounds have been reported. Amongst them, the
8
method of Julian, developed more than 50 years ago, which involved the introduction of a ß-aminoethyl
group equivalent at C-3 of 1,3-dimethyloxindole, (Scheme 1), still remains, in its essentials, an often used
9
synthetic approach to 1 and its analogues.
Herein we report a new formal synthesis of (±)-1 via (±)-3 involving a N-carbomethoxyoxindole as the
starting material and describe our attempts to obtain the eseroline derivative [(±)-2] (R = OCOtBu).
Results and Discussion
The requisite oxindole was readily prepared as follows: chemoselective acylation of N-
phenylhydroxylamine with ClCO Me furnished the hydroxamic acid (4) which was O-acylated (DCC, 4-
2
10
DMAP) by 2-phenylsulfanylpropanoic acid to 5 (Scheme 2).
†
Dedicated to Professor Alberto C. Ralha on the occasion of his 80th birthday.

Similarly 6 gave the tert-butyl ester (7) which was converted into 8.
Me
3 Me
R
R
N
HN
O
Me
Me
N
H
N
Me
Me
Julian's oxindole
1 R = OCONHMe (-)-physostigmine
2 R = OH (-)-eseroline
3 R = H (-)-desoxyeseroline
Scheme 1.
11
A 3,3-sigmatropic rearrangement of the enolates derived from 5 and 8 was studied next for obtaining the
12
precursors of the crucial oxindoles, extending a previously reported protocol.
Me
PhS
R
R
R
O
MeOCOCl
NaHCO
PhSCH(Me)CO H
2
OH
OH
O
N
H
N
N
3
DCC, DMAP
CO2Me
CO2Me
4 R = H
7 R = OCOBu-t
5 R = H
8 R = OCOBu-t
6 R = OCOBu-t
Scheme 2.
Although the enolate (9) (R=H) (Scheme 3) could be readily generated from 5, at low temperature, with
13
KH or lithium diisopropylamide, and a 3,3-sigmatropic rearrangement achieved in satisfactory yield in
14
the presence TMSCl, the best results were obtained with potassium bistrimethylsilylamide (KHMDS)
alone. The presence of the thioether functionality was also found to be crucial for the rearrangement to
occur smoothly. A similar effect was first reported by Lythgoe for systems containing an all carbon
15
framework.
The major products formed were isolated, after acidification, by chromatography and
16
identified as the oxindole (10), the o-aminophenylacetic ester (11) and its p-isomer (12) (Scheme 3).

However, for the subsequent reaction, such separation was unnecessary, since the crude product could be
converted directly into 10, by dehydration (Ac O, NaOAc), and purification effected at this stage. The
2
oxindole (13) was similarly secured from 8 via 14.
Stannyl hydride mediated desulfurisation of 10 and 13 occurred readily and the two oxindoles (15) and
(16) were obtained in 78 and 79% yields respectively.
Me
PhS
Me
PhS
b
R
O
O
R = H
5
8
O
a
O
N
N
CO2Me
CO2Me
9
a
b
1) 3,3-sigmatropic
1) ion-pair
recombination
rearrangement
+
1) ion-pair
recombination
+
R = H
[3,5]
+
2) H O
3
2) H O
3
2) H O
3
Me
PhS
Me
PhS
PhS
HO2C
Me
R
R
CO2H
AcONa
Ac O
NH
CO2Me
O
2
NH
CO2Me
N
12
CO2Me
10 R = H
13 R = OCOBu-t
11 R = H
14 R = OCOBu-t
Scheme 3.
All our attempts to introduce the aminoethyl side chain at C-3, utilising the carbanion generated from 15
17 18
and its subsequent reaction with the electrophile N-carbethoxyaziridine, failed
(Scheme 4). Instead,
amongst a mixture of compounds formed, the hydroxyoxindole (17) (51%) was obtained probably from
the reaction of the carbanion and the adventitious presence of oxygen in the system. However the same
carbanion (derived from 15 and lithium tetramethylpiperidide, LTMP) in THF underwent alkylation with
19
the more powerful electrophile nitroethylene, to provide ß-nitroethyloxindole (18) in excellent yield. For
reasons not clearly understood, a similar alkylation of 16 to 19 occurred, despite various conditions tried,
with disappointingly low yield (14%).

C-Alkylation of enolates, under phase transfer conditions, with chiral quaternary salts, especially those
derived from Cinchona alkaloids, is a powerful method for the generation of chiral quaternary centres.
Application of this procedure to oxindole (15) and nitroethylene in the presence of N-(4-trifluoromethyl-
9f
benzyl)cinchonium bromide, although successful in providing a modest chemical yield of 18 ( 40%),
˜
proceeded with little or no optical induction under a variety of conditions (temp., conc., solvent).
A
probable reason for the failure could be due to the powerful electrophilic nature of nitroethylene, since it is
known that in general the least reactive alkylating agent affords the highest chiral induction (with RCl > RBr
20
> RI). A similar result was obtained using lithium bis-[(R)-1-phenylethyl]amide.
Me
N R
Me
3
R
O
NH
10
13
O
N
CO2Me
CO2Me
20 R = H
21 R = OH
22 R = OMe
15 R = H
16 R = OCOBu-t
1) Base
2)
1) Base
2)
N CO2Et
NO2
Me
NO2
O
Me
NHCO2Et
R
R
O
N
Me
OH
N
CO2Me
CO2Me
O
N
18 R = H
19 R = OCOBu-t
CO2Me
17
Scheme 4.
0
Whilst catalytic reduction of 18 with Pd provided a mixture of pyrrolidone (20) and the hydroxamic acid
(21), characterised as its methyl ester (22), in 8 and 78% yields respectively, hydrogenation with Raney Ni
furnished solely 20 in 76% yield. Direct reductive cyclisation of 20 with LAH did not lead to (±)-
nordesoxyeseroline, possibly due to the presence of free NH groups forming insoluble lithium salts.
Therefore 20 was subjected to the action of MeI (excess) in the presence of NaH (2 eq) (Scheme 5). The

two isomeric urethanes, that were isolated from the reaction, were assigned structures (23) and (24) on the
basis of their spectroscopic properties and MS spectral data. A possible mechanism for the formation of
the oxindole (23) is shown: the deprotonated species (A), in equilibrium with B via C, is N-methylated to
give D. Subsequently D undergoes either intra- or intermolecular acyl transfer to E, which in turn suffers N-
alkylation to generate 23.
Me
N Me
O
NMe
CO2Me
24
MeI
Me
Me
N H
N H
NaH
20
O
O
N
N
CO2Me
CO2Me
C
A
Me
N
Me
Me
NH
MeI
O
N
O
NaH
N
CO2Me
CO2Me
D
Inter- or intramolecular
B
CO Me transfer
2
Me
N
Me
N
Me
Me
MeI
CO2Me
CO2Me
O
O
N
N
Me
E
23
Scheme 5.
Acid hydrolysis of either isomer (23) or (24) furnished the same oxindole (25) (Scheme 6), probably via F
and G.

Reduction of 25 with LAH furnished (±)-desoxyeseroline [(±)-3]. The preparation of (±)-3 constitutes in a
formal sense a synthesis of (±)-physostigmine [(±)-1], since 3 has been converted via (-)-eseroline (2) into
21
1. In conclusion, a novel synthesis of (±)-desoxyeseroline [(±)-3] is disclosed, involving a formal 3,3-
sigmatropic rearrangement of an appropriate O-acyl derivative of an hydroxamic acid. This approach can
readily be adapted to produce differently 3-substituted oxindoles for production of analogues.
Me
Me
23
Me
NH
conc. HCl
reflux
LAH
N
O
Me
N
H
N
Me
24
Me
rac-desoxyeseroline (±)-3
25
Hydrolysis-
decarboxylation
Me
Me
N Me
OH
N Me
O
N
N
H
Me
Me
F
G
Scheme 6.
ACKNOWLEDGMENT
We are grateful to Fundação para a Ciência e a Tecnologia (FC&T, Lisbon, Portugal) for partial financial
support. Two of us (P. F. S. and P. S. A.) also thank FC&T for the award of research fellowships.
EXPERIMENTAL
General: Solvents and reagents were purified and dried according to standard procedures. Hydrogenation
reactions were carried out in a Parr 3911 hydrogenator, at room temperature. Elemental analyses were
carried out with an automatic microanalyzer (Carlo Erba). For TLC, Merck silica gel 60 F
plates were
254
used. Melting points were determined on a Reichert Thermovar apparatus and are uncorrected. NMR:
Varian Unity 300 or Brucker ARX 400 spectrometers, using TMS as internal standard. All spectra were
taken at 300 MHz in CDCl solutions unless stated otherwise. EI-MS: Kratos MS 25 RS or Fisons TRIO
3
2000 spectrometers (70 eV). HR-MS: AutoSpecQ spectrometer. IR: Perkin Elmer 683 or Buck Scientific
-1
500 spectrometers, in KBr, unless stated otherwise (wavenumbers in cm ).
22a
C-Methoxy-N-phenylhydroxamic acid (4): To an ice-cooled solution of N-phenylhydroxylamine
(9.22 g, 84.6 mmol) in anhydrous Et O (125 mL), containing NaHCO (9.0 g, 107.1 mmol), under
2
3

vigorous stirring, was added dropwise a solution of methyl chloroformate (6.6 mL, 85.4 mmol) in the same
solvent (15 mL). The reaction mixture, after being stirred at rt for 2.5 h, was diluted with Et O and filtered
2
to remove the inorganic salts, which were washed with Et O. The combined filtrates were washed with
2
water, dried over anhydrous Na SO , and the solvent removed at reduce pressure to give 4 (13.42 g, 95%),
2
4
as a slightly brownish solid: needles, mp 34-35 °C (Et O/n-hexane). IR: υ = 3210 (br, OH), 1676 (s,
2
1
C=O). H NMR: δ = 7.94 (br s, 1H, OH, exchangeable D O), 7.48 (m, 2H, ArH), 7.36 (m, 2H, ArH),
2
+
7.20 (m, 1H, ArH), 3.81 (s, 3H, OCH ). EI-MS: m/z (%) 167 (15.0) [M ], 151 (13.0), 119 (100.0). HR-
3
MS: C H NO : calcd 167.0582; found: 167.0589.
8 9
3
C-Methoxy-N-phenyl-O-(2-phenylsulfanylpropanoyl)hydroxamic acid (5). A solution of DCC (20.6
g, 99.8 mmol) in anhydrous CH Cl (70 mL) was added dropwise to a solution of 4 (15.85 g, 94.9 mmol), 2-
2 2
10
phenylsulfanylpropanoic acid
(19.0 g, 104.4 mmol), and 4-(N,N-dimethylamino)pyridine (2.35 g, 19.2
mmol), in the same solvent (250 mL), under vigorous stirring at rt. The reaction mixture, after being stirred for
3 h, was filtered under reduced pressure and the filtrate evaporated to dryness. Et O was added to the residue
2
and the resulting mixture filtrated to remove the residual N,N-dicyclohexylurea. The filtrate was
then
washed, sequentially, with 5% aqueous NaHCO , 5% aqueous HCl and water. After drying over anhydrous
3
Na SO , subsequent removal of the solvent at reduced pressure furnished 5 (26.7 g, 85%), as a viscous pale-
2
4
1
yellow oil. IR (neat): υ = 1790 (s, NOCO), 1740 (s, COOMe). H NMR: δ = 7.37-7.20 (m, 10H, ArH), 3.91
(q, J = 7.2 Hz, 1H, CHCH ), 3.80 (s, 3H, OCH ), 1.55 (d, J = 7.2 Hz, 3H, CHCH ). EI-MS: m/z (%) 331
3
3
3
+
(1.9) [M ], 151 (4.9), 137 (9.2), 119 (100.0). HR-MS: C H NO S: calcd 331.0878; found: 331.0889.
17 17
4
23
N-(4-Trimethylacetyloxyphenyl)hydroxylamine (6): To 4-nitrophenyl trimethylacetate (5.0 g, 22.4
mmol) in a EtOH/water mixture (4.3/1) (100 mL), containing ammonium chloride (2.0 g, 37.4 mmol),
stirred vigorously at rt, was slowly added zinc (1.5 g, 22.9 mmol). The addition of zinc was carried out in
such way that the reaction temperature did not exceed 60 °C. After being stirred for 1.5 h, the reaction
mixture was filtered at reduced pressure and the filtrate extracted with CH Cl . The combined organic
2 2
layers were dried over anhydrous Na SO , and the residue recrystallized from benzene and petroleum
4
2
ether to give 6 (1.39 g, 30%) as a pale-yellow solid: needles, mp 119-121 °C. IR: υ = 3290 (br, OH and
1
NH), 1725 (s, C=O). H NMR: δ = 7.01-6.94 (m, 4H, ArH), 6.78 (br s, 1H, NH or OH, exchangeable
D O), 5.49 (br s, 1H, NH or OH, exchangeable D O), 1.35 [s, 9H, C(CH ) ].
3 3
2
2
C-Methoxy-N-(4-trimethylacetyloxyphenyl)hydroxamic acid (7): Hydroxylamine (6) (2.45 g, 11.7
mmol) in anhydrous Et O (50 mL) was acylated with methyl chloroformate (0.91 mL, 11.8 mmol), in dry
2
Et O (5 mL), in the presence of NaHCO (1.18 g, 14.1 mmol), as described above for the preparation of 4
2
3
(1.5 h). Recrystallization of the crude product from Et O and petroleum ether afforded 7 (2.76 g, 88%), as
2
1
a white solid: needles, mp 78-79 °C. IR: υ = 3390 (br, OH), 1740 (s, Me CCO), 1680 (s, COOMe). H
3
NMR δ = 7.67 (br s, 1H, OH, exchangeable D O), 7.46 (d, J = 8.8 Hz, 2H, ArH), 7.03 (d, J = 8.8 Hz, 2H,
2
+
ArH), 3.81 (s, 3H, OCH ), 1.35 [s, 9H, C(CH ) ]. EI-MS: m/z (%) 267 (8.3) [M ], 251 (10.1), 219 (5.5),
3
3 3
183 (22.5), 167 (62.8), 135 (71.6), 107 (17.4), 57 (100.0). Anal. Calcd for C H NO : C, 58.42; H, 6.41;
13 17
5
N, 5.24: Found: C, 58.36; H, 6.45; N, 5.11.

C-Methoxy-N-(4'-trimethylacetyloxyphenyl)-O-(2-phenylsulfanylpropanoyl)hydroxamic acid (8):
Compound (7) (3.48 g, 13.0 mmol) was condensed with 2-phenylsulfanylpropanoic acid (2.8 g, 15.4
mmol), in anhydrous CH Cl (100 mL), in the presence of 4-DMAP (0.32 g, 2.6 mmol) and DCC (2.79 g,
2 2
13.5 mmol) in the same solvent (10 mL), as described above for the preparation of 5 (4 h).
Recrystallization of the resulting residue from Et O and petroleum ether gave 8 (4.90 g, 87%), as a white
2
1
solid: needles, mp 69.5-70.5 °C. IR: υ = 1800 (s, NOCO), 1755 (s, Me CCO), 1730 (s, COOMe). H
3
NMR: δ = 7.38-7.24 (m, 7H, ArH), 7.05 (d, J = 8.7 Hz, 2H, ArH), 3.88 (q, J = 7.4 Hz, 1H, CHCH ),
3
3.78 (s, 3H, OCH ), 1.54 (d, J = 7.4 Hz, 3H, CHCH ), 1.36 [s, 9H, C(CH ) ]. EI-MS: m/z (%) 431 (14.1)
3 3
3
3
+
[M ], 278 (19.6), 267 (31.3), 251 (21.9), 219 (10.9), 183 (7.0), 167 (8.5), 137 (40.7), 135 (23.3), 109
(14.8), 57 (100.0). Anal. Calcd for C H NO S: C, 61.24; H, 5.84; N, 3.25: Found: C, 61.26; H, 5.81; N,
22 25
6
3.12.
Rearrangement of 5: To a suspension of KH (90.6 mmol, 10.38 g of a 35% dispersion, washed free of
the mineral oil with anhydrous THF), in anhydrous THF (110 mL), stirred at rt under N atmosphere, was
2
slowly added bistrimethylsilylamine (19.1 mL, 90.6 mmol). The suspension, after having been stirred for 2
h, was cooled to – 80 °C and a solution of 5 (10.0 g, 30.2 mmol) in the same solvent (40 mL) was added
dropwise. The reaction mixture was stirred for 1 h, while the temperature was allowed to rise slowly to rt,
and then evaporated to dryness at reduced pressure. The residue was dissolved in a mixture of Et O and
2
water, and the organic layer, after having been separated by decantation, extracted with 5% aqueous
NaHCO . The combined aqueous layers were washed with Et O, acidified (pH 1) with 5% HCl and
3
2
˜
extracted with Et O. The combined ethereal extracts were dried over anhydrous Na SO and the solvent
2
2
4
removed at reduced pressure to afford a 6/1 mixture of, respectively, acids (11) and (12) in 89% yield.
Successive recrystallization of the crude mixture from Et O/n-hexane furnished 11 (6.5 g, 65%) as a white
2
solid: mp 127 °C (decomp) (AcOEt/n-hexane). IR: υ = 3270 (br, OH and NH), 1730 (s, COOMe), 1660
1
(s, COOH). H NMR (acetone d ): δ = 8,00 (br s, 1H, NH or OH, exchangeable D O), 7.81 (d, J = 7.8
6
2
Hz, 1H, ArH), 7.38-7.26 (m, 2H, ArH), 7.19-7.14 (m, 2H, ArH), 7.08-7.05 (m, 2H, ArH), 6.91-6.80 (m,
+
2H, ArH), 3.72 (s, 3H, OCH ), 1.91 (s, 3H, CCH ). EI-MS: m/z (%) 313 (15.4) [M -H O], 204 (100.0).
3
3
2
Anal. Calcd for C H NO S: C, 61.61; H, 5.17; N, 4.23: Found: C, 61.65; H, 5.16; N, 4.10.
17 17
4
The ethereal layers, containing the base insoluble products, were dried over anhydrous Na SO and the
2
4
residue subjected to preparative TLC (Et O/n-hexane - 1/1) to give oxindole (10) (0.19 g, 2%) as a white
2
1
solid: mp 108.5-110.5 °C. IR: υ = 1775 (s, NCO), 1735 (s, COOMe). H NMR: δ = 7.67-7.64 (m, 1H,
ArH), 7.44-7.41 (m, 1H, ArH), 7.31-7.11 (m, 7H, ArH), 3.93 (s, 3H, OCH ), 1.74 (s, 3H, CCH ). EI-MS:
3
3
+
m/z (%) 313 (14.3) [M ], 204 (100.0). Anal. Calcd for C H NO S: C, 65.16; H, 4.82; N, 4.47: Found:
17 15
3
C, 65.12; H, 4.78; N, 4.43. Acid (12) was isolated (0.77 g, 7%) from the crude mixture of the two isomeric
acids after conversion of 11 into the corresponding oxindole (10) (as mentioned below), as asolid:mp 131 °C
1
(decomp). IR: υ = 3170 (br, OH and NH), 1750 (s, COOMe), 1690 (s, COOH). H NMR: δ = 9.18
(br s, 1H, OH, exchangeable D O), 7.61-7.58 (m, 2H, ArH), 7.49-7.29 (m, 7H, ArH), 6.38 (br s, 1H, NH,
2
+
exchangeable D O), 3.70 (s, 3H, OCH ), 1.44 (s, 3H, CCH ). EI-MS: m/z (%) 299 (22.2) [M -MeOH],
2
3
3
286 (36.1), 256 (18.9), 222 (22.8), 221 (47.5), 118 (100.0). Anal. Calcd for C H NO S: C, 61.61; H,
17 17
4
5.17; N, 4.23: Found: C, 61.72; H, 5.14; N, 4.11.

Oxindole (10). The crude mixture of acids (11) and (12) (11.06 g, 33.4 mmol) and sodium acetate (270 mg,
3.3 mmol), in acetic anhydride (90 mL), was heated at 60-70 °C for 3 h, concentrated at reduced pressure
and the residue treated, with stirring, with a saturated aqueous solution of NaHCO until pH 8. The
3
˜
mixture was then extracted with Et O and the combined organic layers washed, sequentially, with 5%
2
aqueous NaHCO and water. On drying over anhydrous Na SO , followed by evaporation under reduced
4
3
2
pressure, crystallisation of the resulting solid from Et O/n-hexane gave 10 in 52% yield (5.43 g), which
2
was identical with the sample obtained as mentioned above.
Rearrangement of 8: A solution of 8 (0.3 g, 0.7 mmol) in anhydrous THF (2 mL) was treated with a
suspension of KHMDS (0.42 g, 2.13 mmol) in the same solvent (4 mL), as described above for 5 (13 h).
Recrystallization of the resulting residue from CH Cl and petroleum ether furnished acid 14 (0.21 g,
2 2
70%), as a solid: mp 142.0 °C (decomp). IR: υ = 3280 (br, OH and NH), 1755 (s, Me CCO), 1735 (s,
3
1
COOMe), 1665 (s, COOH). H NMR: δ = 7.92 (br s, 1H, NH or OH, exchangeable D O), 7.51-6.92 (m,
2
7H, ArH), 6.36 (s, 1H, ArH), 3.69 (s, 3H, OCH ), 1.78 (s, 3H, CCH ), 1.25 [s, 9H, C(CH ) ]. EI-MS:
3 3
3
3
+
m/z (%) 413 (18.8) [M -H O], 304 (91.3), 246 (12.3), 220 (37.7), 161 (18.1), 133 (26.8), 110 (52.9), 77
2
(22.5), 57 (100.0). Acid (14) was further characterised as the methyl ester, readily obtained by treatment
22b
of an ethereal solution of the compound with excess ethereal solution of diazomethane,
as a white solid:
mp 112-113 °C (Et O/petroleum ether). IR: υ = 3310 (br, NH), 1750 (s, Me CCO), 1740 (s, COOMe),
2
3
1
1725 (s, NCOOMe). H NMR: δ = 7.68-7.01 (m, 9H, ArH and NH), 6.41 (d, J = 2.4 Hz, 1H, ArH), 3.81
(s, 3H, OCH ), 3.69 (s, 3H, OCH ), 1.83 (s, 3H, CCH ), 1.28 [s, 9H, C(CH ) ]. EI-MS: m/z (%) 445
3
3
3
3 3
+
(8.3) [M ], 413 (100.0). HR-MS: C H NO S: calcd 445.1559; found: 445.1596.
23 27
6
Oxindole (13): Acid (14) (0.72 g, 1.67 mmol) was dehydrated with sodium acetate (13.8 mg, 0.17 mmol),
in acetic anhydride (4 mL), as described for the crude mixture of acids (11) and (12) (2 h). Recrystallization
of the residue from Et O yielded 13 (0.56 g, 81%), as a white solid: mp 106.0-107.5 °C. IR: υ = 1770 (s,
2
1
NCO), 1750 (s, Me CCO), 1740 (s, COOMe). H NMR (400 MHz): δ = 7.63 (d, J = 8.8 Hz, 1H, ArH),
3
7.30-7.23 (m, 3H, ArH), 7.18-7.13 (m, 3H, ArH), 6.92 (dd, J = 2.5, 8.8 Hz, 1H, ArH), 3.92 (s, 3H,
+
OCH ), 1.75 (s, 3H, CCH ), 1.39 [s, 9H, C(CH ) ]. EI-MS: m/z (%) 413 (6.9) [M ], 304 (63.4), 220
3
3
3 3
(15.8), 161 (5.7), 109 (11.7), 77 (7.9), 57 (100.0). Anal. Calcd for C H NO S: C, 63.90; H, 5.61; N, 3.39:
22 23
5
Found: C, 64.29; H, 5.60; N, 3.27.
1-Methoxycarbonyl-3-methyloxindole (15): Compound (10) (2.84 g, 9.07 mmol) and n-Bu SnH (7.3
3
mL, 27.14 mmol) in anhydrous benzene (25 mL), under reflux, was treated (2 h 40 min), through a syringe
pump, with a solution of AIBN (140 mg, 0.85 mmol) in the same solvent (4 mL). After the addition of the
initiator was complete, reflux was continued for 40 min. The solvent was then removed at reduced pressure
and the residue dissolved in a 1/1 mixture of acetonitrile and n-hexane. The acetonitrile layer, after being
separated by decantation, was washed with n-hexane and evaporated to dryness. Recrystallization of the
resulting residue from Et O/n-hexane furnished 15 (1.45 g, 78%), as a white solid: mp 75-76 °C.
2
1
IR: υ = 1760 (s, NCO), 1730 (s, COOMe). H NMR: δ = 7.91 (d, J = 8.1 Hz, 1H, ArH), 7.36-7.17 (m,
3H, ArH), 4.02 (s, 3H, OCH ), 3.61 (q, J = 7.7 Hz, 1H, CHCH , collapses to singlet by irradiation at the
3
3
frequency of 1.54), 1.54 (d, J = 7.7 Hz, 1H, CHCH , collapses to singlet by irradiation at the frequency of
3

+
3.61). EI-MS: m/z (%) 205 (100.0) [M ]. Anal. Calcd for C H NO : C, 64.38; H, 5.40; N, 6.38:
11 11
3
Found: C, 64.71; H, 5.40; N, 6.82.
1-Methoxycarbonyl-3-methyl-5-trimethylacetyloxyoxindole (16): Compound (13) (0.82 g, 1.99 mmol)
was desulfurized with n-Bu SnH (1.6 mL, 5.95 mmol), in anhydrous benzene (25 mL), in the presence of
3
AIBN (32 mg, 0.20 mmol) (solution in 7.5 mL of anhydrous benzene added to reaction mixture for 1.5 h),
as described above (2 h). Recrystallization of the resulting residue from Et O/n-hexane yielded 16 (0.48 g,
2
79%), as a white solid: mp 122.5-124.0 °C. IR: υ = 1780 (s, NCO), 1750 (s, Me CCO), 1730 (s,
3
1
COOMe). H NMR: δ = 7.92 (d, J = 9.6 Hz, 1H, ArH), 7.02-6.98 (m, 2H, ArH), 4.02 (s, 3H, OCH ),
3
3.62 (q, J = 7.6 Hz, 1H, CHCH ), 1.54 (d, J = 7.6 Hz, 1H, CHCH ), 1.37 [s, 9H, C(CH ) ]. EI-MS: m/z
3 3
3
3
+
(%) 305 (9.7) [M ], 221 (41.8), 162 (13.8), 146 (10.5), 119 (25.1), 57 (100.0). Anal. Calcd for
C H NO : C, 62.94; H, 6.27; N, 4.59: Found: C, 62.57; H, 6.26; N, 4.43.
16 19
5
Reaction of 15 with N-ethoxycarbonylaziridine: To a solution of 15 (0.1 g, 0.49 mmol) and N-
17
ethoxycarbonylaziridine (260 mg, 2.26 mmol) in anhydrous THF (10 mL), cooled to -90°C, stirred
under N atmosphere, was added dropwise (1 h) a suspension of KHMDS (0.11 g, 0.57 mmol) in the
2
same solvent (10 mL). The reaction mixture was then stirred for 5 h while the temperature was left to rise
slowly to rt. The solvent was then removed at reduced pressure and the residue dissolved in a mixture of
Et O and 5% aqueous HCl. The organic layer, obtained by decantion, was washed with water and dried
2
over anhydrous Na SO . Removal of the solvent at reduced pressure left a dark residue which was
2
4
subjected to preparative TLC (silica, Et O/n-hexane - 1/1) to give 3-hydroxy-1-methoxycarbonyl-3-
2
methyloxindole (17) (54.7 mg, 51%), as a colorless oil. IR: υ 3450 (br, OH), 1780 (s, NCO), 1740 (s,
=
1
COOMe). H NMR: δ = 7.93 (d, J = 8.4 Hz, 1H, ArH), 7.47-7.36 (m, 2H, ArH), 7.27-7.22 (m, 1H,
13
ArH), 4.02 (s, 3H, OCH ), 2.90 (br s, 1H, OH, exchangeable D O), 1.64 (s, 3H, CCH ). C NMR: δ =
3
2
3
2
3
176.9 (C ), 151.3 (CO Me), 138.3, 130.2, 130.1, 125.4, 123.5, 115.4, 73.5 (C ), 54.0 (OCH ), 25.8 (C -
3
2
3
+
CH ). EI-MS: m/z (%) 221 (100.0) [M ]. HR-MS: C H NO : calcd 221.0688; found: 221.0698.
11 11
3
4
1-Methoxycarbonyl-3-methyl-3-(2'-nitroethyl)oxindole (18): To an ice-cooled solution of 2,2,6,6-
tetramethylpiperidine (1.65 mL, 9.78 mmol) in anhydrous THF (30 mL), stirred under N atmosphere,
2
was added a 1.4 M solution of n-BuLi in n-hexane (7.0 mL, 9.8 mmol). After 30 min, the suspension was
cooled to -80 °C and a solution of 15 (2.0 g, 9.76 mmol) in anhydrous THF (15 mL), followed by a
19
solution of nitroethylene (0.79 g, 10.8 mmol) in anhydrous benzene (6 mL), was added. The reaction
mixture was stirred for 10 min, diluted with Et O and evaporated to dryness. The resulting residue was
2
dissolved in a mixture of Et O and water, and the organic layer, after being separated by decantation, was
2
washed with water and dried over anhydrous Na SO . After removal of the solvent at reduced pressure,
2
4
the residue obtained was recrystallized from Et O/n-hexane, to give 18 (2.25 g, 83%) as a white solid: mp
2
1
78-79.5 °C. IR: υ = 1765 (s, NCO), 1740 (s, COOMe), 1555 (s, NO ), 1355 (s, NO ).
2
H NMR: δ =
2
7.96 (d, J = 8.4 Hz, 1H, ArH), 7.41-7.34 (m, 1H, ArH), 7.28-7.22 (m, 2H, ArH), 4.34-4.24 (m, 1H,
CH CH NO ), 4.17-4.08 (m, 1H, CH CH NO ), 4.04 (s, 3H, OCH ), 2.74-2.64 (m, 1H,
2
2
2
2
2
2
3
CH CH NO ), 2.58-2.48 (m, 1H, CH CH NO ), 1.50 (s, 3H, CCH ). EI-MS: m/z (%) 278 (100.0)
3
2
2
2
2
2
2
+
[M ]. Anal. Calcd for C H N O : C, 56.11; H, 5.07; N, 10.07: Found: C, 56.34; H, 5.05; N, 10.09.
13 14 2 5

1-Methoxycarbonyl-3-methyl-3-(2'-nitroethyl)-5-trimethylacetyloxyoxindole (19): Similarly 16 gave
19 (14%, after recrystallization from Et O and n-hexane), as a white solid: mp 124-125.5 °C. IR: υ = 1770
2
1
(s, NCO), 1750 (s, Me CCO), 1730 (s, COOMe), 1550 (s, NO ), 1355 (m, NO ). H NMR: δ = 7.98 (d, J
3
2
2
= 8.7 Hz, 1H, ArH), 7.06 (dd, J = 2.4, 8.7 Hz, 1H, ArH), 6.98 (d, J = 2.4 Hz, 1H, ArH), 4.35-4.10 (m,
2H, CH CH NO ), 4.04 (s, 3H, OCH ), 2.73-2.63 (m, 1H, CH CH NO ), 2.54-2.43 (m, 1H,
2
2
2
3
2
2
2
+
CH CH NO ), 1.51 (s, 3H, CCH ), 1.37 [s, 9H, C(CH ) ]. EI-MS: m/z (%) 378 (3.9) [M ], 294 (33.8),
3 3
2
2
2
3
260 (3.2), 220 (3.6), 176 (12.5), 162 (5.7), 147 (3.8), 119 (3.1), 85 (10.1), 57 (100.0).
Reaction of 15 with nitroethylene in the presence of N-(4-trifluoromethylbenzyl)cinchonium
bromide (4-CF BCNB): To an ice-cooled mixture of 15 (43.5 mg, 0.21 mmol) and 85% 4-CF BCNB (12
3
3
mg, 0.022 mmol) in toluene (2 mL), stirred vigorously under N atmosphere, was added 25% aqueous NaOH
2
(0.04 mL, 0.25 mmol) followed, 10 min later, by a solution of nitroethylene (81.6 mg, 1.12 mmol), in
anhydrous benzene (0.6 mL) diluted in toluene (2 mL). After being stirred for 20 min, the reaction mixture
was diluted with a mixture of Et O and water and acidified with 5% aqueous HCl. The organic layer, after
2
being separated by decantation, was washed with water, dried over anhydrous Na SO and the solvent
4
2
removed a reduced pressure. The remaining residue was purified by preparative TLC (silica, Et O/n-hexane
2
- 1/1) to give 18 (22.8 mg, 39%), as a white solid, which was identical with a sample previously isolated. The
1
H NMR spectrum of 18 in the presence of the shift reagent Eu(tfc) (splitting of ArH doublet at d 7.69 into
3
two doublets at δ 8.70 and 8.59) indicated ee ≈ 0.
Hydrogenation of 18. a) In the presence of PtO : A solution of 18 (0.4 g, 1.44 mmol) in EtOH (50 mL),
2
containing 80% PtO (41 mg, 0.14 mmol), was shaken under hydrogen pressure (45 Psi) for 26.5 h. After
2
removal of the catalyst by filtration over celite, the filtrate was evaporated to dryness and the residue
recrystallized from Et O and CH Cl to give 1-hydroxy-3-(2’-methoxycarbonylamino)phenyl-3-
2 2
2
methyl-2-pyrrolidone (21) (0.30 g, 78%), as a white solid: mp 165 °C (decomp). IR: υ = 3240 (br, NH
1
and OH), 1720 (s, COOMe), 1675 (s, NCO). H NMR: δ = 9.17 (br s, 2H, NH and OH, exchangeable
D O), 7.59 (br s, 1H, ArH), 7.31-7.25 (m, 2H, ArH), 7.13 (t, J = 7.5 Hz, 1H, ArH), 3.76-3.68 (m, 5H,
2
OCH and CH CH N), 2.68-2.58 (m, 1H, CH CH N), 2.07-1.99 (m, 1H, CH CH N), 1.53 (s, 3H,
2
3
2
2
2
2
2
+
CCH ). EI-MS: m/z (%) 264 (41.2) [M ], 262 (48.4), 248 (19.6), 244 (44.0), 232 (50.8), 216 (48.0), 205
3
(31.8), 204 (52.0), 188 (45.2), 173 (43.8), 160 (36.4), 146 (91.2), 144 (77.6), 130 (100.0). HR-MS:
C H N O : calcd 264.1110; found: 264.1108. Anal. Calcd for C H N O : C, 59.08; H, 6.10; N,
13 16 2 4 13 16 2 4
10.60: Found: C, 58.96; H, 6.11; N, 10.46. Evaporation of the mother-liquors from recrystallization of 21
left a residue which was purified by preparative TLC (silica, Et O/n-hexane - 3/1) to give 3-(2’-
2
methoxycarbonylamino)phenyl-3-methyl-2-pyrrolidone (20) (after recrystallization from Et O and
2
CH Cl , 28 mg, 8%), as a white solid: mp 162 °C (decomp). IR: υ = 3280 (br, NH), 1715 (s, COOMe),
2 2
1
1690 (s, NCO). H NMR: δ = 9.77 (br s, 1H, NH, exchangeable D O), 7.77 (br s, 1H, ArH), 7.31-7.26
2
(m, 2H, ArH), 7.10 (t, J = 7.5 Hz, 1H, ArH), 6.85 (br s, 1H, NH, exchangeable D O), 3.76 (s, 3H,
2
OCH 3.44-3.40 (m, 2H, CH CH N), 2.84-2.76 (m, 1H, CH CH N), 2.19-2.11 (m, 1H, CH CH N), 1.60
3),
2
2
2
2
2
2
13
(s, 3H, CCH ). C NMR: δ = 182.0 (C ), 155.1 (COOMe), 137.2, 132.5, 128.1, 126.1, 125.7, 124.4,
2
3
+
52.2 (OCH ), 47.6, 39.3, 36.6, 22.4. EI-MS: m/z (%) 248 (44.7) [M ], 216 (30.7), 205 (100.0). Anal.
3
Calcd for C H N O : C, 62.89; H, 6.50; N, 11.28: Found: C, 62.75; H, 6.49; N, 11.28. b) In the
13 16 2 3

presence of Raney-Ni: Compound (18) (0.289 g, 1.04 mmol) was dissolved in MeOH (30 mL) and
24
hydrogenated in the presence of Raney-Ni
(
25 mg), as described previously with PtO .
~ 2
Recrystallization of the crude product from Et O and CH Cl furnished 20 (196 mg, 76%), as a white
2 2 2
solid, which was identical with a sample previously isolated.
1-Methoxy-3-(2’-methoxycarbonylamino)phenyl-3-methyl-2-pyrrolidone (22): To an ice-cooled
suspension of KH (0.74 mmol, 85 mg of a 35% dispersion, washed free of oil with anhydrous THF) in
anhydrous THF (4 mL), stirred under N atmosphere, was added a solution of 21 (180.5 mg, 0.73 mmol)
2
in the same solvent (2 mL). Once the evolution of H has ceased, MeI (0.045 mL, 0.73 mmol) was added
2
and the resulting mixture stirred for an additional 30 min at rt. The reaction mixture was then filtered at
reduced pressure to remove the inorganic salt and the filtrate evaporated to dryness. Purification of the
resulting residue by preparative TLC (silica, Et O) furnished 22 (145 mg, 71%, after recrystallization from
2
Et O and CH Cl ), as a white solid: mp 139.5-141.0 °C. IR: υ 3170 (br, NH), 1700 (br and s, COOMe
2 2
2
=
1
and NCO). H NMR: δ = 9.49 (br s, 1H, NH, exchangeable D O), 7.76 (br d, J = 7.5 Hz, 1H, ArH), 7.33-
2
7.26 (m, 2H, ArH), 7.16-7.10 (t, J = 7.5 Hz, 1H, ArH), 3.81 (s, 3H, OCH ), 3.76 (s, 3H, OCH ), 3.70- 3.56
3
3
(m, 2H, CH CH N), 2.70-2.61 (m, 1H, CH CH N), 2.11-2.03 (m, 1H, CH CH N), 1.60 (s, 3H, CCH ).
3
2
2
2
2
2
2
+
EI-MS: m/z (%) 278 (2.5) [M ], 246 (21.0), 216 (13.0), 204 (12.5), 173 (11.0), 172 (11.0), 159 (12.5), 146
(24.0), 130 (100.0). HR-MS: C H N O : calcd 278.1266; found: 278.1271.
14 18 2 4
Methylation of pyrrolidone (20): To an ice-cooled solution of 20 (0.48 g, 1.94 mmol) in anhydrous THF
(12 mL), stirred under N atmosphere, was added a 60% dispersion of NaH in mineral oil (165 mg, 4.13
2
mmol). After the evolution of gas has ceased, MeI (0.26 mL, 4.16 mmol) was added and the resulting
mixture stirred at rt for 4 h 45 min. The reaction mixture was then filtrated over celite and the filtrate
evaporated to dryness at reduced pressure. The residue was dissolved in CH Cl and the solution washed
2 2
with water and dried over anhydrous Na SO . After removal of the solvent by evaporation at reduced
4
2
pressure, the residue was subjected to preparative TLC (Et O) to afford 3-(2'-N-
2
methoxycarbonylmethylamino)ethyl-1,3-dimethyloxindole (23) (174 mg, 32%), as a 1/1 mixture of
25
1
1
two conformers ( H NMR)
NMR: δ = 7.31-7.19 (m, 2H, ArH), 7.09 (t, J = 7.2 Hz, 1H, ArH), 6.85 (br d, J = 7.2 Hz, 1H, ArH,
changes to d at 50 °C), 3.58/3.55 (s/s, 3H, OCH , collapse to s at 50 °C 3.21 (s, 3H, NCH ), 3.18-2.78
(colorless oil). IR (neat): υ = 1705 (br and s, NCO and COOMe). H
3
),
3
(m, 2H, CH CH N, collapses to br s at 50 °C), 2.75/2.73 (s/s, 3H, NCH collapse to s at 50 °C), 2.28-
3
2
2
2.11 (m, 1H, CH CH N), 2.09-1.88 (m, 1H, CH CH N, collapses to br s at 50 °C), 1.37 (s, 3H, CCH ).
3
2
2
2
2
+
EI-MS: m/z (%) 276 (3.1) [M ], 216 (4.7), 201 (7.6), 161 (100.0). HR-MS: C H N O : calcd
15 20 2 3
276.1473; found: 276.1487; and 3-(2'-N-methoxycarbonylmethylamino)phenyl-1,3-dimethyl-2-
25
1
pyrrolidone (24) (310 mg, 58%), as a 4.4/1 mixture of two conformers ( H NMR, see ref. ), (colorless
1
oil). IR: υ = 1700 (br and s, NCO and COOMe). H NMR: δ = 7.51-7.47 (m, 1H, ArH), 7.43-7.26 (m,
2H, ArH), 7.07 (br s, 1H, ArH, changes to m at 50°C), 3.75/3.62 (br s/br s, 3H, OCH , collapse to br s at
3
50 °C 3.50-3.23 (m, 2H, CH CH N), 3.21/3.06 (s/s, 3H, NCH ), 2.95/2.93 (s/s, 3H, NCH ), 2.80-1.85
),
2
2
3
3
+
(m, 2H, CH CH N, 1.60/1.58 (s/s, 3H, CCH ). EI-MS: m/z (%) 276 (100.0) [M ]. HR-MS:
2
2
3
C H N O : calcd 276.1473; found: 276.1484.
15 20 2 3

1,3-Dimethyl-3-(2'-methylaminoethyl)oxindole (25). a) By hydrolysis of 24: To 24 (40 mg, 0.14
mmol) was added conc. HCl (2.5 mL) and the mixture heated under reflux for 15 h. The reaction mixture
was cooled, diluted with water, washed with Et O, basified with NaHCO and extracted with CHCl .
2
3
3
The combined organic layers were dried over anhydrous Na SO and the solvent removed under reduced
2
4
pressure. Recrystallization of the resulting residue from Et O/n-hexane furnished 25 (28.4 mg, 93%), as a
2
8b
1
white solid: mp 79-81 °C (lit., mp 87 °C). IR (neat): υ = 3320 (br, NH), 1710 (s, C=O). H NMR: δ =
7.29-7.25 (m, 1H, ArH), 7.19 (d, J = 7.5 Hz, 1H, ArH), 7.07 (t, J = 7.5 Hz, 1H, ArH), 6.85 (d, 1H, J =
7.5 Hz, ArH), 3.21 (s, 3H, NCH ) 2.26 (s, 3H, NCH ), 2.24-1.94 (m, 4H, CH CH ), 1.37 (s, 3H,
3 ,
3
2
2
+
CCH ). EI-MS: m/z (%) 218 (7.3) [M ], 174 (6.4), 161 (27.5), 160 (30.3), 144 (11.9), 130 (17.4), 77
3
(19.3), 58 (100.0). HR-MS: C H N O: calcd 218.1419; found: 218.1449. b) By hydrolysis of 23: The
13 18 2
hydrolysis of 23 (174.5 mg, 0.63 mmol) with conc. HCl (10 mL), carried out as above, furnished 25 (131
mg, 95%), which was identical with a sample prepared by method a).
(±)-Desoxyeseroline [(±)-3]: To an ice-cooled solution of 25 (474 mg, 2.17 mmol) in anhydrous THF (10
mL), stirred under N atmosphere, was added LiAlH (161 mg, 4.24 mmol) and the suspension stirred at
2
4
rt overnight. The mixture was then cooled in an ice bath and 5 N aqueous NaOH (5 mL) was slowly added.
The resulting mixture was heated under reflux for 1 h and then extracted with boiling AcOEt. The combined
organic layers were extracted with 10% aqueous HCl and the combined aqueous layers neutralized with 5 N
aqueous NaOH. This mixture was extracted with CHCl and the combined organic layers washed with water
3
and dried. After removal of the solvent at reduced pressure, the residue was purified by column
chromatography (Et O) to yield (±)-3 (302.5 mg, 69%), as a yellowish oil. IR (neat): υ = 1605, 1495,
2
26
1
1450, 1345, 1300, 1255, 1120, 1035, 1020, 955, 735. H NMR: δ = 7.08 (dt, J = 1.1, 7.5 Hz, 1H,
ArH), 7.00 (dd, J = 1.1, 7.5 Hz, 1H, ArH), 6.68 (dt, J = 1.1, 7.5 Hz, 1H, ArH), 6.42 (d, J = 7.5 Hz, 1H,
ArH), 4.12 (s, 1H, NCHN), 2.95 (s, 3H, NCH ), 2.77-2.59 (m, 2H, CH CH N), 2.55 (s, 3H, NCH ), 1.99-
3
2
2
3
13
1.95 (m, 2H, CH CH N), 1.44 (s, 3H, CCH ). C NMR: δ = 151.9, 136.6, 127.7, 122.2, 117.5, 106.6,
2
2
3
8a
97.5 (C ), 53.2 (C ), 52.7 (C ), 40.8 (C ), 38.4 (C H ), 36.5 (C H ), 27.3 (C H ). EI-MS: 202 (100.0)
2
3a
3
8
1
3a
3
3
3
+
[M ]. HR-MS: C H N : calcd 202.1469; found: 202.1476. The picrate of (±)-3, obtained as yellow
8b
13 18 2
crystals, after recrystallization from EtOH, had: mp 182.5-184 °C (lit., mp 179-180 °C). IR: υ = 1635,
1
1615, 1565 (s, NO ), 1490, 1430, 1360, 1320 (s, NO ), 1275, 1165, 1075, 1005, 910, 785, 740. H NMR: δ
2
2
= 11.30 (br s, 1H, NH), 8.93 (s, 2H, ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH), 7.11 (d, J = 7.2 Hz,
6.92 (t, J = 7.2 Hz, 1H, ArH), 6.66 (d, J = 7.2 Hz, 1H, ArH), 5.16 (d, J = 3.0 Hz, 1H, NCHN), 3.71-3.65 (m,
1H, CH CH N), 3.19 (s, 3H, NCH ), 2.83 (d, J = 4.5 Hz, 3H, NCH ), 2.71-2.61 (m, 1H, CH CH N), 2.57-
1H, ArH),
2
2
3
3
2
2
2.47 (m, 1H, CH CH N), 2.35-2.30 (m, 1H, CH CH N), 1.55 (s, 3H, CCH ).
3
2
2
2
2
REFERENCES AND NOTES
‡
E-mail: aml@mail.fct.unl.pt (A. M. Lobo); sp@dq.fct.unl.pt (S. Prabhakar)
1.
S. Takano and K. Ogasawara, 'The Alkaloids', Vol. 36, ed. by A. Brossi, Academic Press, New
York, 1989, pp. 225-251.
2.
3.
U. Axelsson, Acta Ophtalmol., Suppl., 1969, 102, 1.
M. B. Walker, Proc. R. Soc. Med., 1934, 1, 1200.

4.
M. Kawabuchi, A. F. Boyne, S. S. Deshpande, W. M. Cintra, A. Brossi, and E. X. Albuquerque,
Synapse, 1988, 2, 139.
5.
6.
A. Brossi, X.-F. Pei, and N. H. Greig, Aust. J. Chem., 1996, 49, 171.
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Davis, W. G. Rosen, B. S. Greenwald, M. I. Levy, and T. B. Horvath, N. Engl. J. Med., 1983,
308, 721. d) L. J. Thal and P. A. Fuld, N. Engl. J. Med., 1983, 308, 720. e) L. J. Thal, P. A. Fuld,
D. M. Masur, and N. S. Sharpless, Ann. Neurol., 1983, 13, 491. f) R. C. Mohs, B. M. Davis, B. S.
Greenwald, A. A. Mathé, C. A. Johns, T. B. Horvath, and K. L. Davis, J. Am. Geriatr. Soc.,
1985, 33, 749.
7.
a) A. Galli, G. Renzi, A. Bartolini, R. Bartolini, and P. Malmberg-Aiello, J. Pharm. Pharmacol.
Commun., 1979, 31, 784. b) A. Bartolini, G. Renzi, A. Galli, P. Malmberg-Aiello, and R.
Bartolini,
Neurosci. Lett., 1981, 25, 179. c) S. Fürst, T. Friedmann, A. Bartolini, R. Bartolini, P. Malmberg-
Aiello, A. Galli, G. T. Somogyi, and J. Knoll, Eur. J. Pharmacol., 1982, 83, 233. d) M. F. Siddiqui
and A. I. Levey, Drugs Fut., 1999, 24, 417.
8.
9.
a) P. L. Julian and J. Pikl, J. Am. Chem. Soc., 1935, 57, 563. b) P. L. Julian and J. Pikl, J. Am.
Chem. Soc., 1935, 57, 539. c) P. L. Julian and J. Pikl, J. Am. Chem. Soc., 1935, 57, 755.
Racemic syntheses after the last review (cf. ref 1): a) P. A. Grieco and W. A. Carroll, Tetrahedron
Lett., 1992, 33, 4401. b) Q.-S. Yu, B.-Y. Lu, and X.-F. Pei, Heterocycles, 1994, 39, 519. c) X.-F.
Pei and S. Bi, Heterocycles, 1994, 39, 357. d) P. F. Santos, A. M. Lobo, and S. Prabhakar,
Tetrahedron Lett., 1995, 36, 8099. e) H. Ishibashi, T. Kobayashi, N. Machida, and O. Tamura,
Tetrahedron, 2000, 56, 1469. Chiral syntheses after the last review: f) T. Matsuura, L. E.
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2
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16.
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17.
18.
It was shown however that an aziridinium ion is sufficiently reactive to undergo ring opening
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19.
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The observation of conformational isomerism in carbamic acid esters, resulting from restricted
1
rotation of the C-N bond, by H NMR is a well-known phenomena. For some examples see: a)
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1
The chemical shifts observed for this compound ( H NMR) were in full agreement with the
26.
recorded values, see: R. Smith and T. Livinghouse, Tetrahedron, 1985, 41, 3559.