First stereoselective synthesis and assignment of the absolute configuration of the nebracetam eutomer and derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.04.012

(-)-Nebracetam 1 was stereoselectively prepared for the first time, allowing the determination of its absolute configuration as (R). The pivotal intermediate in the synthesis, 1-benzyl-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-pyrrolidin-2-one 6, was previously obtained in 60% yield and 90% ee from an enoate derived from d-mannitol. Two approaches were investigated to synthesize (R)-(-)-nebracetam 1 and analogues 4 and 5 from 6. Compound 6 was transformed into WEB-1868 2. Mesylation of the hydroxyl group in 2, followed by nucleophilic substitution with azide and reduction led to target 1. Compounds 4 and 5 were synthesized by using morpholine and N-methyl piperazine as nucleophiles. Compounds 4 and 5 were also prepared, in higher yields and similar ee, through the reductive amination of aldehyde 10, obtained in two steps from 6.

Full text of DOI:10.1016/j.tetasy.2008.04.012

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1161–1165
First stereoselective synthesis and assignment of the absolute
configuration of the nebracetam eutomer and derivatives
Evanoel C. Lima,a Jorge L. O. Domingos,a Ayres G. Diasb,* and Paulo R. R. Costaa,*
a
ˆ
´
ˆ
´
Laborato´rio de Quı´mica Bioorganica (LQB), Nucleo de Pesquisas de Produtos Naturais, Centro de Ciencias da Saude, Bloco H,
Ilha da Cidade Universita´ria, Universidade Federal do Rio de Janeiro, 21941-590 Rio de Janeiro, Brazil
b
ˆ
Departamento de Quı´mica Organica, Instituto de Quımica, Universidade do Estado do Rio de Janeiro,
´
20550-900 Rio de Janeiro, Brazil
Received 19 February 2008; accepted 2 April 2008
Available online 13 May 2008
Abstract—(ꢀ)-Nebracetam 1 was stereoselectively prepared for the first time, allowing the determination of its absolute configuration as
(R). The pivotal intermediate in the synthesis, 1-benzyl-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-pyrrolidin-2-one 6, was previously
obtained in 60% yield and 90% ee from an enoate derived from D-mannitol. Two approaches were investigated to synthesize (R)-(ꢀ)-
nebracetam 1 and analogues 4 and 5 from 6. Compound 6 was transformed into WEB-1868 2. Mesylation of the hydroxyl group in
2, followed by nucleophilic substitution with azide and reduction led to target 1. Compounds 4 and 5 were synthesized by using mor-
pholine and N-methyl piperazine as nucleophiles. Compounds 4 and 5 were also prepared, in higher yields and similar ee, through
the reductive amination of aldehyde 10, obtained in two steps from 6.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
N
HO
H2N
O
The pyrrolidin-2-one nucleus is embedded in the structure
of several bioactive compounds.1a–e Some of these sub-
stances substituted at C-4 display outstanding biological
activities, such as (R)-rolipram, a potent and selective
PDE4 inhibitor2a–c and a HIV-1 replication inhibitor.2d
4-Substituted derivatives have also been used as intermedi-
ates in the synthesis of pyrrolidines, such as a selective
agonist of HT3 histaminic receptors,1b and c-amino
acids, such as (R)-baclofen.1c–e Nebracetam 1,3a–e its fuma-
rate salt (WEB-1881),3f as well as WEB-1868 23g and 3
(Fig. 1) act as nootropic agents3h and are hailed as smart
drugs. These increase the faculties of the mind like bolster-
ing cognition, lucidity, memory and mood.3h,i Nebracetam
1 is awaiting marketing approval in Japan to be used as a
cognitive enhancer3a,b and acts as a partial agonist at the
presynaptic muscarinic receptor. Dopaminergic and sero-
tonergic uptakes are also reduced by 1, and intracellular
calcium flux is inhibited in response to glutaminergic stim-
O
N
O
O
N
N
F
1
3
2
N
N
O
N
O
O
N
N
Me
4
5
Figure 1. Nebracetam, (R)-(ꢀ)-1, and analogues.
ulation.3b These pyrrolidones are promising for the preven-
tion and symptomatic treatment of degenerative senior’s
diseases, and were patented as antidepressant drugs.4 The
enantiomers of 1 were obtained by chemical resolution
and the levo isomer proved to be 10 times more active than
the dextro one,3b,j but its absolute configuration was not
determined. On the other hand, the enantiomers of 2 were
*
Corresponding authors. Tel.: +55 021 2562 6791; fax: +55 021 25626791
(P.R.R.C.); e-mail addresses: ayresdias@click21.com.br; lqb@nppn.
ufrj.br
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.012

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E. C. Lima et al. / Tetrahedron: Asymmetry 19 (2008) 1161–1165
almost equipotent3e and for compound 3, no correlation
between biological activity and configuration was done.
OH
HO
ii
O
O
i
Herein, we report the first stereoselective synthesis of (ꢀ)-1,
allowing the determination of its configuration as R. New
derivatives of 1 (Fig. 1), (R)-(ꢀ)-4 and (R)-(ꢀ)-5, were also
stereoselectively synthesized by two different approaches.
O
N
Bn
9
O
iii
N
Bn
6
HO
O
N
+
X
N
iv
O
N
Bn
2. Results and discussion
O
O
N
Bn
N
Bn
11
We had previously reported the synthesis of homochiral
compound 6 from a Z-enoate derived from D-(+)-manni-
tol, in three steps and 52% overall yield. This compound
was used as an intermediate in the synthesis of (S)-(ꢀ)-
WEB-1868 2.5a In Scheme 1, the use of this alcohol as a
precursor of (ꢀ)-nebracetam 1 and derivatives5b (ꢀ)-4,
(ꢀ)-5 is shown. Alcohol 2 was mesylated under the stan-
dard conditions, leading to 7 in 96% yield.6 Nucleophilic
substitution of the mesylate group in 7 by azide6 in DMF
(90%), followed by the reduction of the crude resulting
intermediate 8 with Na2S6 in solution of methanol–water
(79%), led to the most active enantiomer (eutomer) of
(ꢀ)-nebracetam 1, and to the establishment of its absolute
configuration as (R). Once alcohol 2 was obtained in good
enantiomeric excess, (95:5 as determined by Mosher ester
analysis) and as its transformation into (ꢀ)-1 does not in-
volve the stereogenic centre, we can conclude that both
products have the same enantiomeric purity.7 Compound
4 was obtained from 7 in 55% yield by reflux in dioxan
in the presence of morpholine for long periods of time
(ꢁ20 h). The yield was improved (86%) when the reaction
was carried out in the absence of the solvent. Compound
5 was prepared by the same strategy in 70% yield (Scheme
1).
10
v
vi
X
N
NH2
O
N
Bn
O
N
Bn
4, X=O
5, X=NMe
(R)-(-)-1a
Scheme 2. Alternative synthesis of 1, 4 and 5. Reagents and conditions: (i)
HCl 6 M, MeOH, 84%; (ii) NaIO4, H2O–MeOH, 94%; (iii) HCl, MeOH,
NaBH3CN and morpholine (4, 87%) or N-methylpiperazine (5, 93%); (iv)
NH2OHꢂHCl, NaHCO3, Na2SO4, CH2Cl2, 89%, (E:Z, 84:16); (v)
AcONH4, NaBH3CN, MeOH, <10%; (vi) NaBH3CN, MeOH, pH 3,
<10%.
next step (Scheme 2). Under the conditions of reductive
amination,8 10 reacted either with morpholine or with N-
methylpiperazine leading directly to 4 or 5, respectively,
in 87% and 93% yield. Unfortunately, under modified
Leukart condition, 10 led to 1 in poor yields (<10% by
GC–MS). Attempts at partial reduction of oxime 11 to
N-hydroxinebracetam furnished nebracetam, instead, in
low yields. The yield of 1 could not be improved using ex-
cess NaBH3CN.
We attempted to shorten the synthesis and improve the
overall yield by directly using aldehyde 10 as a precursor
of the target molecules. The hydrolysis of the dimethylketal
group at 6, followed by the oxidation of the resulting diol 9
with NaIO4 led to 10, which was immediately used in the
The specific rotations of compounds 4 and 5 prepared by
reductive amination from 10 were found to be very similar
to those obtained for these compounds when synthesized
from alcohol 2, showing that the reductive amination of
10 occurs without racemization.
OH
O
O
ref. 5a
3. Conclusion
O
N
Bn
2
O
N
Bn
6
Herein, we have reported the first enantioselective synthesis
of nebracetam (ꢀ)-1, allowing the (R)-configuration to be
established for this compound. Analogues (ꢀ)-4 and (ꢀ)-
5 were also enantioselectively prepared from 6, in either
four steps, via nucleophilic substitution (Scheme 1, 45–
55% overall yield), or, more conveniently and efficiently,
in three steps by means of reductive amination (Scheme
2, 73–87% overall yield).
i
OMs
X
N
H2N
N3
iii
iv
ii
O
N
Bn
O
O
O
N
N
Bn
N
Bn
Bn
4, X=O
7
(R)-(-)-1a
5, X=NMe
8
Since key compound 6 can also be obtained in its enantio-
meric form from vitamin C,9 the disclosed synthetic strat-
egy represents a broad access to pyrrolidin-2-ones with
different patterns of substitution and configuration at the
4-position.
Scheme 1. Synthesis of (ꢀ)-1, (ꢀ)-4 and (ꢀ)-5 from chiral compound 6.
Reagents and conditions: (i) MsCl, Et3N, CH2Cl2, 96%; (ii) NaN3, DMF,
100 °C, 90%; (iii) Na2S, MeOH, H2O, 79%; (iv) morpholine, neat, 86% or
N-methylpiperazine, neat, 70%.

E. C. Lima et al. / Tetrahedron: Asymmetry 19 (2008) 1161–1165
1163
4. Experimental
(200 MHz, CDCl3) d (ppm): 7.39–7.05 (m, 5H), 4.45 (d,
1H, J = 14.6 Hz), 4.33 (d, 1H, J = 14.6 Hz), 3.61–3.50
(m, 2H), 3.37 (dd, 1H, J = 9.8 Hz; 8.2 Hz), 3.09 (dd, 1H,
J = 9.8 Hz; 4.8 Hz), 2.60–2.39 (m, 2H), 2.36–2.18 (m,
1H); 13C NMR (50 MHz, CDCl3) d (ppm): 174.2, 135.8–
127.3, 63.9, 49.1, 46.3, 33.7, 32.8. MS (EI, 70 eV): m/z
205 (%) (43, M+), 174 (6), 146 (28), 114 (23), 104 (26), 91
(100), 65 (31), 55 (13).
4.1. N-Benzyl-(4S)-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
pyrrolidin-2-one 6
To a mixture of the syn-nitroadduct obtained by conjugate
addition of nitromethane to the enoate derived from D-
mannitol10 (260 mg, 1.0 mmol) and Pd/C 10% (65 mg,
25% w/w) in methanol was added ammonium formate
(760 mg, 12.0 mmol).11 The reaction mixture was submit-
ted to sonication for 2 h (total disappearance of the starting
material detected by TLC). The crude mixture was filtered
through Celite and the solvent evaporated in vacuo. The
resulting material was purified by flash column chromato-
graphy with methanol–ethyl acetate (5:95) to give a solid
in 86% yield (160 mg). A solution of this compound in
dry THF (1.8 mL) was added dropwise to a suspension
of NaH (31 mg, 1.3 mmol) in THF (6.5 mL). After 1 h,
BnBr was added (192.0 mg, 1.12 mmol) in THF (1.1 mL)
and the mixture was stirred at rt for 24 h. The excess of
NaH was destroyed by the addition of brine (10.0 mL)
and the resulting mixture was extracted with CH2Cl2
(5 ꢃ 15.0 mL). The organic phases were mixed, dried over
Na2SO4, filtered and concentrated in vacuo to give a pale
solid in 87% yield (206 mg). [a]D = ꢀ4.4 (c 2.0, CHCl3);
1H NMR (200 MHz, CDCl3) d (ppm): 7.39–7.19 (s, 5H),
4.47 (d, 1H, J = 14.7 Hz), 4.24 (d, 1H, J = 14.7 Hz),
3.60–3.16 (s, 5H), 2.60–2.10 (s, 3H); 13C NMR (50 MHz,
CDCl3) d (ppm): 173.0, 135.9–127.4, 109.1, 77.4, 67.4,
48.7, 46.3, 34.3, 33.3, 26.3, 25.0. MS (EI, 70 eV): m/z 275
(11), 218 (11), 202 (26), 173 (36), 91 (100), 65 (13).
4.4. N-Benzyl-(4S)-4-methanesulfonylmethyl-pyrrolidin-
2-one 7
A solution of 2 (0.10 g, 0.48 mmol) and triethylamine
(0.06 mL, 0.58 mmol) in CH2Cl2 (4.8 mL) was cooled to
0 °C. Mesyl chloride (0.08 g, 0.55 mmol) was added drop-
wise over 15 min to the vigorously stirred solution. The
reaction mixture was allowed to stir for an additional
15 h at rt after the addition of mesyl chloride had been
completed. To this solution was added 15.0 mL of CH2Cl2
and the resulting slurry was washed with 3 ꢃ 8.0 mL por-
tions of saturated aqueous sodium bicarbonate, followed
by 3 ꢃ 8.0 mL portions of water. The organic layer was
dried, filtered and evaporated to an orange oil, mesylate
7 (0.13 g, 96%). Mesylate 7 was converted to azide 8, with-
1
out further purification. [a]D = ꢀ3.0 (c 2.36, CHCl3); H
NMR (200 MHz, CDCl3) d (ppm): 7.38–7.20 (m, 5H),
4.42 (s, 2H), 4.16 (dd, 1H, J = 9.9 Hz; 5.9 Hz), 4.09–4.04
(m, 1H), 3.41 (dd, 1H, J = 10.2 Hz; 8.1 Hz), 3.09 (dd,
1H, J = 10.2 Hz; 4.8 Hz), 2.94 (s, 3H), 2.80–2.72 (m, 1H),
2.62 (dd, 1H, J = 16.5 Hz; 9.2 Hz), 2.26 (dd, 1H, J =
16.5 Hz; 5.5 Hz); 13C NMR (50 MHz, CDCl3) d (ppm):
172.2, 135.6–127.3, 70.1, 48.2, 46.0, 36.8, 33.1, 30.2; MS
(EI, 70 eV): m/z 283 (%) (26, M+), 254 (5), 146 (20), 119
(33), 96 (33), 91 (100), 65 (25), 55 (13).
4.2. N-Benzyl-(4S)-4-[(10S)-10,20-dihydroxyethyl]pyrrolidin-
2-one 9
To a solution of 5 (140 mg, 0.51 mmol) in MeOH (4.5 mL)
was added aqueous 6 N HCl (0.04 mL) at room tempera-
ture. After stirring for 3 h, the solvent was removed in va-
cuo and the material obtained was dissolved in CH2Cl2
(10.0 mL), dried with K2CO3 and filtered. Removal of sol-
vent gave 9 as a solid (106 mg, 84%), which was used for
the next step without purification. [a]D = ꢀ15.0 (c 2.1,
4.5. N-Benzyl-(4S)-4-azidomethyl-pyrrolidin-2-one 8
Mesylate 7 (93 mg, 0.33 mol) was dissolved in 2.0 mL of
DMF, followed by the addition of sodium azide (33 mg,
0.50 mmol) and the resulting solution was heated at
100 °C for 7 h, leading to a complete consumption of 7.
The reaction mixture was cooled to rt, after which
8.0 mL of saturated brine was added and the solution
was extracted with 5 ꢃ 15 mL portions of ethyl acetate.
The combined organic layer was washed with 2 ꢃ 8.0 mL
portions of water, dried and then evaporated, furnishing
a yellow oil, azide 8 (70 mg, 90%). The crude product
was used to prepare (ꢀ)-1. [a]D = +2.2 (c 0.90, CHCl3);
1H NMR (200 MHz, CDCl3) d (ppm): 7.39–7.15 (m, 5H),
4.44 (s, 2H), 3.42–3.23 (m, 3H), 3.02 (dd, 1H, J =
10.1 Hz; 5.13 Hz), 2.68–2.45 (m, 2H), 2.32–2.10 (m, 1H);
13C NMR (50 MHz, CDCl3) d (ppm): 172.9, 135.8–127.4,
54.1, 49.2, 46.3, 34.6, 30.9; (EI, 70 eV): m/z 230 (%)
(8, M+), 202 (4), 173 (15), 118 (12), 91 (100), 65 (27), 56
(16).
1
CHCl3); H NMR (200 MHz, CDCl3) d (ppm): 7.34–7.10
(m, 5H), 4.47 (d, 1H, J = 14.7 Hz), 4.24 (d, 1H, J =
14.7 Hz), 3.65–3.16 (m, 5H), 2.58–2.20 (m, 3H); 13C
NMR (50 MHz, CDCl3) d (ppm): 174.2, 135.5–127.3,
73.4, 64.4, 48.7, 46.2, 33.7, 33.5. MS (EI, 70 eV): m/z 235
(%) (21, M+), 146 (14), 119 (9), 91 (100), 65 (18).
4.3. N-Benzyl-(4S)-4-hydroxymethyl pyrrolidin-2-one
(2, WEB-1868)
To a solution of diol 9 (70 mg, 0.30 mmol) in H2O–MeOH
(3:1, 3.2 mL) was added NaIO4 (90 mg, 0.40 mmol). After
stirring for 1.5 h at room temperature, the mixture was
cooled to 0 °C and NaBH4 (15 mg, 0.39 mmol) was added.
After stirring for 3 h, the mixture was extracted with
CH2Cl2 (5 ꢃ 12 mL). The organic layers were dried over
sodium sulfate, the solvent was removed in vacuo and the
residue was purified by flash column chromatography
(MeOH–ethyl acetate, 1:9) affording alcohol 2 as an
4.6. N-Benzyl-(4R)-4-aminomethyl pyrrolidin-2-one (ꢀ)-1
(nebracetam)
Azide 8 (54 mg, 0.24 mmol) was dissolved in 0.6 mL of
CH3OH and a solution of Na2S (24 mg, 0.31 mmol) in
1
oil (42 mg, 79%). [a]D = ꢀ10.1 (c 1.0, CHCl3); H NMR

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E. C. Lima et al. / Tetrahedron: Asymmetry 19 (2008) 1161–1165
1.2 mL of H2O was added. The two-phase mixture was
heated to 65 °C and stirred at that temperature overnight.
The resulting homogeneous orange solution was saturated
with NaCl and extracted with 5 ꢃ 6.0 mL portions of
CH2Cl2. The combined organic layers were dried, filtered
and evaporated to furnish the (R)-nebracetam (ꢀ)-1
4.9. N-Benzyl-(4R)-4-N-methyl-piperazylmethyl pyrrolidin-
2-one 5
4.9.1. Procedure A, nucleophilic substitution. A mixture of
7 (33.8 mg, 0.12 mmol) and N-methyl piperazine (0.5 mL)
was stirred for 38 h at rt. The reaction mixture was parti-
tioned between 15 mL of ethyl acetate and water
(2 ꢃ 10 mL). The organic layer was dried over Na2SO4, fil-
tered and evaporated to furnish 5 (24,2 mg, 70%).
1
(40 mg, 79%), as an oil. [a]D = ꢀ6.3 (c 1.90, CHCl3); H
NMR (200 MHz, CDCl3) d (ppm): 7.38–7.20 (m, 5H),
4.44 (s, 2H), 3.38 (dd, 1H, J = 9.9 Hz; 7.9 Hz), 3.00 (dd,
1H, J = 9.9 Hz; 5.4 Hz), 2.76 (dd, 1H, J = 12.5 Hz;
6.7 Hz), 2.66 (dd, 1H, J = 12.5 Hz; 7.1 Hz), 2.61 (dd,
1H), 2.48–2.28 (m, 1H), 2.20 (dd, 1H, J = 16.1 Hz;
6.1 Hz); 13C NMR (50 MHz, CDCl3) d (ppm): 173.8,
136.2–127.3, 54.8, 50.0, 45.7, 35.6, 35.2, 34.1; MS (EI,
70 eV): m/z (%) 204 (3, M+), 187 (56), 174 (9), 106 (9), 91
(100), 65 (24), 56 (12).
1
[a]D = ꢀ5.7 (c 1.3, CHCl3). H NMR (200 MHz, CDCl3)
d (ppm): 7.37–7.21 (m, 5H), 4.45 (s, 2H), 3.37 (dd, 1H,
J = 9.9 Hz; 7.6 Hz), 3.04 (dd, 1H, J = 9.9 Hz; 4.8 Hz),
2.40–2.20 (m, 12H), 2.20–2.08 (m, 4H); 13C NMR
(50 MHz, CDCl3) d (ppm): 173.9, 136.4, 128.5–127.4,
62.1, 54.7, 52.8, 50.6, 46.4, 45.6, 35.8, 29.5, 28.7; MS (EI,
70 eV): m/z % 287 (6, M+), 243 (2), 174 (7), 113 (100), 91
(17), 70 (57).
4.7. N-Benzyl-4-[(10S)-carboxyaldehyde]pyrrolidin-2-one 10
4.9.2. Procedure B, reductive amination. To a solution of
57.1 mg (0.57 mmol) of N-methyl piperazine in 0.7 mL of
absolute MeOH was added 0.04 mL (0.19 mmol) of 5 N
To a solution of diol 9 (70 mg, 0.30 mmol) in H2O–MeOH
(3:1, 3.2 mL) was added NaIO4 (90 mg, 0.40 mmol). After
stirring for 1.5 h, the mixture was extracted with CH2Cl2
(5 ꢃ 15 mL), dried with Na2SO4 and filtered. Removal of
solvent afforded 10 (54 mg, 94%), which was used for the
reductive amination and formation of oxime 11 without
purification.
HCl–methanol, followed by
a solution of 19.4 mg
(0.095 mmol) of aldehyde 10 in 0.5 mL of MeOH and
6.0 mg (0.095 mmol) of NaBH3CN. The mixture was stir-
red 30 h at room temperature. Concentrated HC1 was
added until pH < 2, and the methanol was removed in va-
cuo. The residue was taken up in 10 mL of water and ex-
tracted with three 12-mL portions of CH2Cl2. The
aqueous solution was brought to pH > 10 with solid
KOH, saturated with NaCl, and extracted with five 15-
mL portions of CH2Cl2. The combined extracts were dried
over Na2SO4 and evaporated to give 25.5 mg (93%) of 5
pure (analyzed by GC–MS, 1H and 13C NMR).
[a]D = ꢀ5.0 (c 0.17, CHCl3).
4.8. N-Benzyl-(4R)-4-morpholylmethyl-pyrrolidin-2-one 4
4.8.1. Procedure A, nucleophilic substitution. A mixture of
7 (34 mg, 0.12 mmol) and morpholine (0.5 mL) was stirred
for 38 h at rt. The reaction mixture was partitioned be-
tween 15 mL of ethyl acetate and water (2 ꢃ 10 mL). The
organic layer was dried over Na2SO4, filtered and evapo-
rated to furnish 4 as an oil (28 mg, 86%). [a]D = ꢀ4.0 (c
2.76, CHCl3); 1H NMR (200 MHz, CDCl3) d (ppm):
7.34–7.22 (m, 5H), 4.44 (s, 2H), 3.64 (t, 4H, J = 4.7); 3.34
(dd, 1H, J = 9.8 Hz; 7.7 Hz), 3.06 (dd, 1H, J = 9.8 Hz;
4.9 Hz); 2.64–2.03 (m, 9H); 13C NMR (50 MHz, CDCl3)
d (ppm): 173.9, 136.3–127.4, 66.7, 53.6, 50.5, 46.4, 35.7,
29.6, 28.3. MS (EI, 70 eV): m/z % 274 (1, M+), 243 (7),
100 (100), 91 (27), 65 (6), 56 (19).
4.10. N-Benzyl-(4S)-4-carbadolxime-pyrrolidin-2-one 11
To a solution of 10 (50 mg, 0.26 mmol) in CH2Cl2 were
added NH2OHꢂHCl (20 mg, 0.30 mmol), NaHCO3
(30 mg, 0.30 mmol) and Na2SO4. This mixture was stirred
for 18 h, filtered and evaporated to furnish oxime 11 as
an oil (50 mg, 89%, E:Z = 84:16) which was used for the
reduction step without further purification. [a]D = +14.0
(c 1.00, CHCl3) 1H NMR (200 MHz, CDCl3) d (ppm):
7.40–7.04 (m, 11H), 6.68 (d, 1H, J = 5.9), 4.49 (d, 2H,
J = 15.6 Hz), 4.39 (d, 2H, J = 15.6 Hz), 3.75–3.60 (m,
2H), 3.59–3.38 (m, 2H), 3.27–3.06 (m, 2H), 2.79 (dd, 2H,
J = 17.2 Hz; 9.2 Hz), 2.42 (dd, 2H, J = 17.2 Hz; 7.3 Hz);
13C NMR (50 MHz, CDCl3) d (ppm): 173.5, 151.7 and
150.0, 135.6–127.6, 49.9 and 49.4, 46.5, 35.2 and 34.8,
31.9 and 27.4. MS (EI, 70 eV): Z-oxime m/z (%) 218 (6,
M+), 201 (13), 146 (6), 118 (9), 91 (100), 65 (21), 51 (7);
E-oxime m/z (%) 200 (42), 160 (2), 146 (44), 132 (5), 118
(20), 104 (43), 91 (100), 65 (39), 51 (19).
4.8.2. Procedure B, reductive amination. To a solution of
79.3 mg (0.91 mmol) of morpholine in 1.0 mL of absolute
MeOH was added 0.06 mL (0.302 mmol) of 5 N HCl–
methanol, followed by a solution of 30.7 mg (0.151 mmol)
of aldehyde 10 in 0.5 mL of MeOH and 9.5 mg
(0.151 mmol) of NaBH3CN. The mixture was stirred 30 h
at room temperature. Concentrated HC1 was added until
pH < 2, and the methanol was then removed in vacuo.
The residue was taken up in 10 mL of water and extracted
with three 12-mL portions of CH2Cl2. The aqueous solu-
tion was brought to pH > 10 with solid KOH, saturated
with NaCl and extracted with five 15-mL portions of
CH2Cl2. The combined extracts were dried over Na2SO4
and evaporated to give 36.2 mg (87%) of 4 pure (analyzed
by GC–MS, 1H and 13C NMR). [a]D = ꢀ4.9 (c 0.30,
CHCl3).
Acknowledgements
The authors thank CNPq, CAPES, FAPERJ, PRONEX;
´
Central Analıtica/NPPN, Professor Simon Garden and
CNRMN Jiri Jonas for analytical data. The authors also

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Jpn. J. Pharmacol. 1999, 80, 9; (f) Prous, J.; Castaner, R. M.;
˜
thank Professor Alessandro B. C. Simas for helpful
suggestions.
Graul, A. Drugs Future 1993, 18, 18; (g) Weber, K.-H. et al.
U.S. Patent, 4,581,364, April 8, 1986; (h) Balaraman, R.;
Shingala, J. Indian J. Pharmacol 2002, 34, 439; (i) Mashkov-
skii, M. D.; Glushkov, R. G. Pharm. Chem. J. 2001, 35, 179;
(j) Yamada, H.; Kushiko, K.; Kohno, Y.; Furukawa, T. Oyo
Yakuri 1996, 51, 29.
References
1. (a) Gouliaev, A. H.; Senning, A. Brain Res. Rev. 1994, 19,
180; (b) Aslanian, R. Tetrahedron: Asymmetry 2000, 11, 3867;
(c) Corey, E. J.; Zhang, F. Y. Org. Lett. 2000, 2, 4257; (d) Zu,
L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Adv. Synt. Catal
2007, 349, 2660; (e) Paraskar, A. S.; Sudalai, A. Tetrahedron
2006, 62, 4907.
4. Lehr, E. et al. U.S. Patent, 4,954,516, 1990.
5. (a) Domingos, J. L. O.; Lima, E. C.; Dias, A. G.; Costa, P. R.
R. Tetrahedron: Asymmetry 2004, 15, 2313; (b) Weber, K.-H.
et al. U.S. Patent 4,767,759, 1988.
6. Gibson, F. S.; Park, M. S.; Rapoport, H. J. Org. Chem. 1994,
59, 7503.
2. (a) Palfreyman, M. N. Prog. Med. Chem. 1996, 33, 2; (b)
Anada, M. et al. Synlett 1999, 11, 1775; (c) Enderes, S.;
Angel, J. B.; Saget, B. M.; Walsh, S. P.; Greten, T. F.;
Dinarello, C. A.; Skolnik, P. R. AIDS 1995, 9, 1137; (d)
Connolly, N. C.; Riddler, S. A.; Rinaldo, C. R. AIDS Rev.
2005, 7, 168; (e) Albrecht, D.; Bach, T. Synlett 2007, 10, 1557.
3. (a) Shorvon, S. Lancet 2001, 358, 1885; (b) Gualtieri, F.;
Manetti, D.; Romanelli, M. N.; Ghelardini, C. Curr. Pharm.
Des. 2002, 8, 125; (c) Weber, K.-H. et al. U.S. Patent
5,073,671, 1991.; (d) Weber, K.-H. et al. U.S. Patent,
4,581,364, 1986; (e) Yamada, K.; Ren, X.; Nabeshima, T.
7. The [a]D reported in literature (Ref. 1c) for 1a in water was
ꢀ8.4. In our work [a]D was measured in CHCl3 (c, 1.90) and a
smaller value was obtained (ꢀ6.3).
8. (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897; (b) Lane, C. F. Synthesis 1975, 135.
9. Hubschwerlin, C. Synthesis 1986, 962.
10. Pinto, A. C.; Freitas, C. B. L.; Dias, A. G.; Pereira, V. L. P.;
Tinant, B.; Declercq, J.-P.; Costa, P. R. R. Tetrahedron:
Asymmetry 2002, 13, 1025.
11. Ehrenkaufer, R. E.; Ram, S. Tetrahedron Lett. 1984, 25, 415.