Synthesis of a conformationally restricted analog of pregabalin by stereoselective alkylation of a chiral pyrrolidin-2-one

Article abstract of DOI:10.1016/S0957-4166(03)00599-8

The 4-benzyloxymethyl pyrrolidin-2-one, 5, was alkylated leading to 3,4-trans-disubstituted pyrrolidin-2-one 6 in good yield and total diastereoselection, as shown by ¹H NMR data and NOE experiments. After reduction of the carbonyl group to giv

Full text of DOI:10.1016/S0957-4166(03)00599-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3353–3358
Synthesis of a conformationally restricted analog of pregabalin
by stereoselective alkylation of a chiral pyrrolidin-2-one
Roberta Galeazzi, Gianluca Martelli, Giovanna Mobbili, Mario Orena* and Samuele Rinaldi
Dipartimento di Scienze dei Materiali e della Terra-Universita` Politecnica delle Marche-Via Brecce Bianche-I-60131 Ancona,
Italy
Received 11 July 2003; accepted 18 July 2003
Abstract—The 4-benzyloxymethyl pyrrolidin-2-one, 5, was alkylated leading to 3,4-trans-disubstituted pyrrolidin-2-one 6 in good
1
yield and total diastereoselection, as shown by H NMR data and NOE experiments. After reduction of the carbonyl group to
give the trans-3,4-disubstituted pyrrolidine 7, and removal of the chiral auxiliary, followed by protection of the nitrogen with
t-Boc group, the corresponding N-protected pyrrolidine, 8 was obtained. The cleavage of the benzyl ether moiety, followed by
oxidation of the hydroxy function, gave in good yield the corresponding pyrrolidine carboxylic acid 2, a restricted analog of
pregabalin.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
mationally restricted non-proteinogenic amino acids,
we considered that appropriate starting materials could
be the hydroxymethyl pyrrolidin-2-ones 3 and 4,4 whose
synthesis was carried out taking advantage of the
recently described cyclisation of acyclic malonamides
mediated by Mn(III) (Scheme 2).5
Pregabalin 1, a potent anticonvulsant related to the
inhibitory neurotransmitter g-aminobutyric acid, repre-
sents a very important drug active in pre-clinical models
in treatment of epilepsy and other neuropathologies
which displays high affinity for the a2d component of
voltage gated ion channels.1 In order to investigate the
binding properties of pregabalin towards its receptor,
the conformationally restricted analog 2 and its enan-
tiomer, ent-2, were required (Scheme 1).2
2. Results and discussion
Although alkylation of N-benzyl lactams was reported
to proceed in poor yield,6,7 our synthetic approach to
compound 2 began with the alkylation of 5, obtained
by reaction of the anion of 3 with benzyl bromide.
Deprotonation at C-3, carried out with LiHDMS, fol-
lowed by treatment with 2-methyl-3-iodopropane,
resulted in the formation in good yield of the 3,4-disub-
stituted derivative 6, exclusively, whose configuration
was established as trans on the basis of the NOE
Many strategies have recently been reported in order to
prepare 4-substituted 3-pyrrolidine carboxylic acids,
since these compounds display an important role in
medicinal chemistry, being the heterocyclic nucleus of
many biologically active compounds, but good stereo-
chemical control of the products has rarely been
attained.3 Within a project aimed to synthesise confor-
between H-3 and CH6 2OBn (8%) (Scheme 3).
Scheme 1.
* Corresponding author. Tel.: +39-71-2204720; fax: +39-71-2204714;
e-mail: orena@mta01.unian.it
Scheme 2.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00599-8

3354
R. Galeazzi et al. / Tetrahedron: Asymmetry 14 (2003) 3353–3358
3. Experimental
3.1. General methods and materials
Melting points were measured on a Electrothermal IA
9000 apparatus and are uncorrected. Infrared spectra
were recorded on a Nicolet 20-SX FT-IR spectrophoto-
1
meter in CHCl3. H and 13C NMR spectra were deter-
mined on a Varian Gemini 200 spectrometer in CDCl3
(unless otherwise reported). Chemical shifts are
reported in the l scale and coupling constants (J)
values are given in Hz. Diastereomeric purity was deter-
mined by GLC analysis by using a Chrompack 9001
gas-chromatograph equipped with a capillary column
Chrompack 7720 (50 m×0.25 mm i.d.; stationary phase
CP-Sil-5 CB). Specific rotation measurements, [h]D,
were recorded at rt on a Perkin–Elmer Model 241
polarimeter at the sodium D line (concentration in
g/100 mL). MS analyses were obtained on a Hewlett–
Packard spectrometer model 5890, series II. Column
chromatography was performed using Kieselgel 60
Merck (230–400 mesh ASTM). Tetrahydrofuran was
distilled from sodium/benzophenone under an argon
Scheme 3. Reagents and conditions: (i) n-BuLi THF, HMPA,
0°C, then benzyl bromide, 91%; (ii) LiHDMS, THF, 0°C,
then 2-methyl-3-iodopropane, 92%.
With the 3,4-trans-disubstituted pyrrolidin-2-one 6 in
hand, removal of the carbonyl group, performed by
using LAH in refluxing THF, gave the N-phenylethyl
substituted pyrrolidine, 7, which underwent nitrogen
debenzylation on treatment with chloroethyl chlorofor-
mate and the N-dealkylated pyrrolidine was directly
converted into the corresponding Boc derivative, 8.8
The cleavage of the benzyl ether, carried out by
hydrogenolysis,9 afforded the alcohol 9 which under-
went oxidation by using the Jones’ reagent,10 leading in
good yield to the carboxylic acid. For better purifica-
tion this compound was directly adsorbed on IRA 900
in the hydroxide form and the carboxylate on poly-
meric support was treated with iodomethane, to give
the ester 10.11 Removal of both the Boc and the methyl
ester groups, carried out by treating with aqueous HCl,
gave the hydrochloride 11 which was eventually con-
verted into the pyrrolidine carboxylic acid 2 by eluting
on Dowex 50WX2 resin with 1 M NH4OH (Scheme 4).
It is worth mentioning that the above synthetic
sequence, carried out starting from 4, gave the amino
acid ent-2 in good yield, so that both the pregabalin
analog, 2, and its enantiomer, ent-2, can be available by
using the stereoselective alkylation of a chiral pyrro-
lidin-2-one (Scheme 5). This approach should be useful
for the synthesis of a number of 4-substituted pyrro-
lidine carboxylic acids, compounds which display an
interesting biological activity.
atmosphere.
(4S,1%S)-4-Hydroxymethyl-1-(1%-phenyl-
ethyl)pyrrolidin-2-one 3 and its diastereomer (4R,1%S)-4
were prepared according to Ref. 4.
3.2. (4S,1%S)-4-Benzyloxymethyl-1-(1%-phenylethyl)-
pyrrolidin-2-one 5
To a solution containing pyrrolidin-2-one 3 (2.2 g; 10
mmol), HMPA (2 mL) and triphenylmethane (100 mg)
in dry THF (30 mL), n-BuLi (2.5 M in hexanes; 4.0
mL) was added at −15°C. After 20 min benzyl bromide
(1.7 g; 10 mmol) dissolved in dry THF (10 mL) was
added and then the mixture was refluxed for 1 h. The
reaction mixture was poured in H2O (100 mL) and
extracted with ethyl acetate (3×100 mL). After drying
(Na2SO4), the solvent was removed under reduced pres-
sure and the residue was purified by silica gel chro-
matography (cyclohexane:ethyl acetate 50:50) to give
compound 5 in 91% yield. Colorless oil. IR (CHCl3):
1
1665 cm−1; H NMR: 1.48 (d, 3H, J=7.0), 2.16–2.32
Scheme 4. Reagents and conditions: (i) LiAlH4, refluxing THF, 78%; (ii) CH3CH(Cl)OCOCl, refluxing DCM, refluxing MeOH,
then Boc2O, Et3N, DMAP, DCM, 76%; (iii) Pd–C 10%, HCOOH, EtOH, 82%. (iii) Jones’ reagent, −10°C, then IRA 900 in the
hydroxide form, CH3I, refluxing cyclohexane, 81%; (v) 3 M HCl, rt, 74%; (vi) Dowex 50WX2, 1 M NH4OH, 64%.

R. Galeazzi et al. / Tetrahedron: Asymmetry 14 (2003) 3353–3358
3355
Scheme 5. Reagents and conditions: (i) n-BuLi THF, HMPA, 0°C, then benzyl bromide, 93%; (ii) LiHDMS, THF, 0°C, then
2-methyl-3-iodopropane, 91%; (iii) LiAlH4, refluxing THF, 77%; (iv) CH3CH(Cl)OCOCl, refluxing DCM, refluxing MeOH, then
Boc2O, Et3N, DMAP, DCM, 79%; (v) Pd–C 10%, HCOOH, EtOH, 80%; (vi) Jones’ reagent, −10°C, then IRA 120 in the
hydroxide form, CH3I, refluxing cyclohexane, 78%; (vii) 3 M HCl, rt 72%; (viii) Dowex 50WX2, 1 M NH4OH, 62%.
(m, 1H), 2.41–2.64 (m, 2H), 3.08 (dd, 1H, J=7.2,
J=9.9), 3.16 (dd, 1H, J=5.6, J=9.9), 3.35 (dd, 1H,
J=6.8, J=9.1), 3.45 (dd, 1H, J=5.4, J=9.1), 4.50
(ABq, 2H, J=13.2), 5.48 (q, 1H, J=7.0), 7.1–7.45 (m,
10 ArH); 13C NMR: 16.6, 31.9, 35.2, 45.8, 49.4, 127.6,
128.0, 128.2, 128.3, 128.8, 129.0, 129.1, 138.4, 140.6,
173.8; [h]D −79.4 (c 1, CHCl3); MS (EI): m/z 309 (M+),
294, 105, 91, 77. Anal. calcd for C20H23NO2: C, 77.64;
H, 7.49; N, 4.53. Found: C, 77.58; H, 7.45; N, 4.59.
10 ArH); 13C NMR: 16.4, 22.4, 23.6, 26.7, 38.7, 40.7,
43.5, 44.4, 49.2, 72.3, 73.7, 127.5, 127.6, 127.8, 128.1,
128.2, 128.9, 129.0, 138.5, 140.8, 176.4; [h]D −75.2 (c 1,
CHCl3); MS (EI): m/z 366 (M++1), 350, 203, 188, 105,
91. Anal. calcd for C24H31NO2: C, 78.87; H, 8.55; N,
3.83. Found: C, 78.81; H, 8.49; N, 3.88.
3.4. (3S,4S,1%S)-4-Benzyloxymethyl-3-(2%%-methylprop-
1%%-yl)-1-(1%-phenylethyl)pyrrolidine 7
3.3. (3S,4S,1%S)-4-Benzyloxymethyl-3-(2%%-methylprop-
1%%-yl)-1-(1%-phenylethyl)pyrrolidin-2-one 6
To a solution containing the pyrrolidin-2-one 6 (3.7 g;
10 mmol) in dry THF (40 mL), LiAlH4 (0.78 g; 20
mmol) was added under an inert atmosphere and the
mixture was refluxed for 3 h. Then MeOH (5 mL) and
an aqueous saturated NH4Cl solution (30 mL) were
added and the mixture was extracted with ethyl acetate
(3×100 mL). After drying (Na2SO4), the solvent was
removed under reduced pressure and the residue was
purified by silica gel chromatography (cyclohex-
ane:ethyl acetate 50:50) to give the pyrrolidine 7 in 78%
To a solution of pyrrolidin-2-one 5 (3.1 g; 10 mmol) in
dry THF (30 mL), LiHMDS (1 M solution in hexanes;
10 mL; 10 mmol) was added dropwise at −15°C under
an argon atmosphere. After stirring for 20 min, a
solution of 1-iodo-2-methylpropane (1.8 g; 10 mmol)
dissolved in dry THF (10 mL) was added at −15°C and
the mixture was stirred for a further 2 h. Then the
reaction mixture was poured in H2O (100 mL) and
extracted with ethyl acetate (3×100 mL). The organic
layer was washed with water, dried (Na2SO4) and evap-
orated. The crude oil was purified by silica gel chro-
matography (cyclohexane:ethyl acetate 50:50) to give
the pyrrolidin-2-one 7 in 92% yield as a colourless oil.
1
yield as a colourless oil. H NMR: 0.86 (d, 3H, J=6.5),
0.87 (d, 3H, J=6.5), 1.23–1.35 (m, 2H), 1.35 (d, 3H,
J=6.6), 1.41–1.59 (m, 1H), 1.78–2.05 (m, 3H), 2.40 (dd,
1H, J=4.7, J=9.4), 2.53 (dd, 1H, J=8.0, J=9.4), 2.94
(dd, 1H, J=6.9, J=8.5), 3.16 (q, 1H, J=6.6), 3.31–3.46
(m, 2H), 4.48 (ABq, 2H, J=12.2), 7.16–7.41 (m, 10
ArH); 13C NMR: 22.8, 23.8, 27.0, 39.3, 45.2, 57.0, 59.8,
66.2, 73.5, 74.4, 127.2, 127.6, 127.7, 127.9, 128.0, 128.7,
128.8, 139.1, 146.2; [h]D −38.6 (c 0.7, CHCl3); MS (EI):
m/z 352 (M++1), 336, 309, 204, 105, 91. Anal. calcd for
C24H33NO: C, 82.00; H, 9.46; N, 3.98. Found: C, 81.93;
H, 9.49; N, 3.94.
1
IR (CHCl3): 1667 cm−1; H NMR: 0.90 (d, 3H, J=6.3),
0.92 (d, 3H, J=6.3), 1.27 (ddd, 1H, J=5.2, J=8.5,
J=14.0), 1.48 (d, 3H, J=7.1), 1.61–1.91 (m, 2H), 2.09–
2.22 (m, 1H), 2.23–2.36 (m, 1H), 3.01 (dd, 1H, J=7.6,
J=9.9), 3.09 (dd, 1H, J=5.7, J=9.9), 3.37 (dd, 1H,
J=7.8, J=9.1), 3.49 (dd, 1H, J=5.0, J=9.1), 4.50
(ABq, 2H, J=12.0), 5.47 (q, 1H, J=7.1), 7.19–7.42 (m,

3356
R. Galeazzi et al. / Tetrahedron: Asymmetry 14 (2003) 3353–3358
3.5. (3S,4S)-3-Benzyloxymethyl-1-(t-butoxycarbonyl)-4-
(2%-methylprop-1%-yl)pyrrolidine 8
added at −15°C and the mixture was stirred for 5 min.
Then ethyl acetate (20 mL) and subsequently Na2CO3
saturated aqueous solution (20 mL) were added at 0°C.
After extraction of the aqueous phase with ethyl acetate
(50 mL), organics were discarded and the pH of the
aqueous layer raised to 2 by slow addition of 1 M HCl
under stirring. Then, extraction with ethyl acetate (2×50
mL) followed by drying (Na2SO4) and removal of the
solvent under reduced pressure gave a residue which
was dissolved in methanol (5 mL). This solution was
added to a suspension of Amberlite IRA 900 in the
hydroxide form (2.0 g) in methanol (10 mL). After 1 h
the solvent was filtered off, the polymeric reagent was
suspended in cyclohexane (15 mL) and CH3I (1.8 g; 13
mmol) was added. The mixture was refluxed for 1.5 h,
then the resin was removed by filtration and the solvent
evaporated under reduced pressure, to give a residue
which was purified by silica gel chromatography (cyclo-
hexane:acetate 70:30) affording the ester 10 in 81%
overall yield as a colourless oil. IR (CHCl3): 1734, 1711
cm−1; 1H NMR: 0.89 (d, 6H, J=6.2), 1.12–1.56 (m,
3H), 1.45 (s, 9H), 2.38–2.54 (m, 1H), 2.54–2.73 (m, 1H),
2.87–2.97 (m, 1H), 3.40–3.52 (m, 1H), 3.55–3.77 (m,
2H), 3.71 (s, 3H); 13C NMR: 21.6, 23.0, 26.2, 26.6, 28.1,
39.5 (70%), 40.1 (30%), 41.8, 48.1 (70%), 49.1 (30%),
50.9, 51.5, 78.9, 153.8, 172.9; [h]D −38.2 (c 3.4, CHCl3);
MS (EI): m/z 285 (M+), 270, 228, 117. Anal. calcd for
C15H27NO4: C, 63.13; H, 9.54; N, 4.91. Found: C,
63.08; H, 10.02; N, 4.86.
To a solution of 7 (1.8 g; 5 mmol) in DCM (20 mL)
chloroethyl chlorocarbonate (1.4 g; 10 mmol) was
added at 0°C and after 20 min the solvent was removed
under reduced pressure. Then to the residue methanol
(40 mL) was added and the solution was refluxed for 30
min. Methanol was removed under reduced pressure
and to the residue ethyl acetate (100 mL) and 2 M
NaOH (50 mL) were added. After extraction with ethyl
acetate (2×100 mL), the organic layer was dried
(Na2SO4) and eventually the solvent was removed
under reduced pressure. The residue was dissolved in
DCM (30 mL) containing Et3N (0.5 g; 5 mmol) and
DMAP (0.1 g) and then di-tert-butyl dicarbonate (1.1
g; 5 mmol) was added at 0°C. After 4 h, H2O (20 mL)
was added and the mixture extracted with ethyl acetate
(2×50 mL). After drying (Na2SO4) and removal of the
solvent under reduced pressure, the residue was purified
by silica gel chromatography (cyclohexane:ethyl acetate
1
70:30) to give 8 in 76% yield as a colourless oil. H
NMR: 0.87 (d, 3H, J=6.2), 0.89 (d, 3H, J=6.2),
1.11–1.35 (m, 2H), 1.47 (s, 9H), 1.49–1.62 (m, 1H),
1.88–2.16 (m, 2H), 2.81–3.01 (m, 1H), 3.03–3.25 (m,
1H), 3.30–3.45 (m, 1H), 3.45–3.71 (m, 3H), 4.51 (ABq,
2H, J=12.2), 7.24–7.42 (m, 5 ArH); 13C NMR: 22.3,
24.1, 27.1, 29.0, 38.4 (60%), 39.2 (40%), 42.7, 44.5
(40%), 45.4 (60%), 49.5 (40%), 49.9 (60%), 51.9 (60%),
52.2 (40%), 71.4, 73.6, 79.4, 127.9, 128.8, 138.7, 154.9;
[h]D −27.2 (c 1, CHCl3); MS (EI): m/z 348 (M++1), 291,
246, 185, 91, 57. Anal. calcd for C21H33NO3: C, 72.58;
H, 9.57; N, 4.03. Found: C, 72.50; H, 9.51; N, 4.10.
3.8. (3S,4S)-4-(2%-Methylprop-1%-yl)-3-pyrrolidine car-
boxylic acid, 2
The ester 10 (0.85 g; 3 mmol) was suspended in 3 M
HCl (5.0 mL) and the mixture was stirred for 24 h at rt.
Removal of H2O under reduced pressure gave a solid
which was recrystallised from methanol to give (3S,4S)-
4-(2%-methylprop-1%-yl)-3-pyrrolidine carboxylic acid
hydrochloride, 11, in 74% yield. Mp 186–188°C. 1H
NMR: 0.87 (m, 6H), 1.28–1.72 (m, 3H), 2.51–2.76 (m,
1H), 2.83–3.15 (m, 2H), 3.45–3.74 (m, 3H). 13C NMR:
24.3, 25.2, 28.9, 43.2, 44.0, 50.1, 51.0, 53.4, 178.8. [h]D
−36.7 (c 1.0, H2O). This product was subjected to ion
exchange column (Dowex 50WX2) and eluted with 1 M
NH4OH to give 2 as a white solid (0.33 g; 64% yield).
3.6. (3S,4S)-1-(t-Butoxycarbonyl)-3-hydroxymethyl-4-
(2%-methylprop-1%-yl)pyrrolidine 9
To a solution containing compound 8 (2.4 g; 7 mmol)
and HCOOH (7 mL) in dry ethanol (60 mL) under an
argon atmosphere, Pd 10 wt. % on activated carbon
(1.4 g) was added and the mixture was stirred for 1 h at
rt. After removal of the catalyst by filtration, the
organic layer was evaporated under reduced pressure
and the residue was dissolved in ethyl acetate (50 mL).
The solution was washed with saturated aqueous
NaHCO3 (30 mL), the solvent was dried (Na2SO4) and
removed under reduced pressure gave pure 9 in 82%
yield. 1H NMR: 0.88 (d, 3H, J=6.2), 0.90 (d, 3H,
J=6.2), 1.13–1.56 (m, 3H), 1.45 (s, 9H), 1.87–2.08 (m,
2H), 2.77–2.97 (m, 1H), 3.05–3.22 (m, 1H), 3.35–3.88
(m, 4H+OH); 13C NMR: 21.8, 23.5, 26.5, 28.5, 37.5
(50%), 38.1 (50%), 42.2, 46.2 (50%), 47.0 (50%), 48.7
(50%), 49.1 (50%), 51.4 (50%), 51.8 (50%), 63.3, 79.2,
154.6; [h]D −39.8 (c 4.0, CHCl3); MS (EI): m/z 257
(M+), 226, 200, 140, 101, 57. Anal. calcd for
C14H27NO3: C, 65.33; H, 10.57; N, 5.44. Found: C,
65.28; H, 10.52; N, 5.51.
1
Mp 243–245°C (Lit.2 251–254°C); H NMR (CD3OD):
0.79–0.94 (m, 6H), 1.18–1.36 (m, 1H), 1.49–1.66 (m,
2H), 2.38–2.62 (m, 2H), 2.72–2.90 (m, 1H), 3.32–3.53
(m, 3H); 13C NMR (CD3OD): 21.1, 22.1, 26.3, 40.8,
41.8, 48.4, 50.1, 51.8, 177.5; [h]D −43.6 (c 0.5, MeOH)
(Lit.2 −45.8); MS (CI): m/z 172 (M++1). Anal. calcd for
C9H17NO2: C, 63.13; H, 10.01; N, 8.18; Found: 62.93;
H, 10.14; N, 8.01.
3.9. (4R,1%S)-4-Benzyloxymethyl-1-(1%-phenylethyl)-
pyrrolidin-2-one 12
This product was prepared in 93% yield from 4 as a
colourless oil by the method described for compound 5.
3.7. Methyl (3S,4S)-1-t-butoxycarbonyl-4-(2%-methyl
prop-1%-yl)-3-pyrrolidinecarboxylate 10
1
IR (CHCl3): 1671 cm−1; H NMR: 1.55 (d, 3H, J=7.1),
2.13–2.28 (m, 1H), 2.48–2.67 (m, 2H), 2.83 (dd, 1H,
J=4.2, J=9.8), 3.20 (dd, 1H, J=7.4, J=9.1), 3.33 (dd,
1H, J=5.4, J=9.1), 3.43 (dd, 1H, J=7.7, J=9.8), 4.39
To a solution containing compound 9 (1.0 g; 4 mmol)
in acetone (20 mL), the Jones’ reagent (1.9 mL) was

R. Galeazzi et al. / Tetrahedron: Asymmetry 14 (2003) 3353–3358
3357
(s, 2H), 5.50 (q, 1H, J=7.1), 7.14–7.42 (m, 10 ArH);
3.15. (3R,4R)-4-(2%-Methylprop-1%-yl)-3-pyrrolidine car-
13C NMR: 16.6, 31.9, 35.2, 45.7, 49.4, 72.6, 79.8, 127.6,
128.0, 128.1, 128.2, 128.9, 129.0, 129.6, 138.3, 140.6,
173.9; [h]D −38.4 (c 1, CHCl3); MS (EI): m/z 309 (M+),
294, 105, 91, 77. Anal. calcd for C20H23NO2: C, 77.64;
H, 7.49; N, 4.53. Found: C, 77.60; H, 7.52; N, 4.50.
boxylic acid hydrochloride, ent-11
This product was prepared in 72% yield from ent-10 by
the method described for compound 11. [h]D +36.9 (c
1.0, H2O).
3.16. (3R,4R)-4-(2%-Methylprop-1%-yl)-3-pyrrolidine car-
boxylic acid, ent-2
3.10. (3R,4R,1%S)-4-Benzyloxymethyl-3-(2%%-methylprop-
1%%-yl)-1-(1%-phenylethyl)pyrrolidin-2-one 13
This product was prepared in 62% yield from ent-11 by
the method described for compound 2. White solid. Mp
235–237°C (Lit.2 236–239°C); [h]D +43.8 (c 0.5, MeOH)
(Lit.2 +44.8).
This product was prepared in 91% yield from 12 as a
colourless oil by the method described for compound 6.
1
IR (CHCl3): 1670 cm−1; H NMR: 0.91 (d, 3H, J=6.5),
0.94 (d, 3H, J=6.5), 1.33 (ddd, 1H, J=5.2, J=8.1,
J=13.3), 1.51 (d, 3H, J=7.2), 1.59–1.91 (m, 2H), 2.20–
2.36 (m, 2H), 2.78 (dd, 1H, J=4.8, J=10.0), 3.20 (dd,
1H, J=7.8, J=9.1), 3.33–3.46 (m, 2H), 4.37 (ABq, 2H,
J=11.9), 5.49 (q, 1H, J=7.2), 7.15–7.41 (m, 10 ArH);
13C NMR: 16.6, 22.4, 23.7, 26.3, 38.6, 40.8, 43.8, 44.3,
49.4, 72.4, 73.7, 127.6, 127.9, 128.1, 128.2, 128.9, 129.0,
138.4, 140.7, 176.6; [h]D −56.1 (c 1, CHCl3); MS (EI):
m/z 366 (M++1), 350, 203, 188, 105, 91. Anal. calcd for
C24H31NO2: C, 78.87; H, 8.55; N, 3.83. Found: C,
78.83; H, 8.58; N, 3.78.
Acknowledgements
We thank M.I.U.R. (Rome, Italy) for financial support
within the PRIN 2002 programme.
References
1. (a) Yuen, P.; Kanter, G. D.; Taylor, C. P.; Vartanian, M.
G. Bioorg. Med. Chem. Lett. 1994, 4, 823–826; (b) Field,
M. J.; McCleary, S.; Hughes, S.; Singh, L. Pain 1999, 80,
391–398; (c) Williams, M.; Kowaluk, E. A.; Arneric, S. P.
J. Med. Chem. 1999, 42, 1481–1500; (d) Stringer, J. L.;
Taylor, C. P. Epilepsy Res. 2000, 41, 155–162; (e) Lydi-
ard, R. B.; Feltner, D. E.; Robinson, P. Liu-Dumaw, M.;
Pande, A. C. Neuropsychopharmacol. 2000, 11, Suppl. 3,
S159–S160; (f) Bialer, M.; Johannessen, S. I.; Kupferberg,
H. J.; Levy, R. H.; Loiseau, P.; Perucca, E. Epilepsy Res.
2001, 43, 11–58; (g) Maneuf, Y. P.; Hughes, J.; Mc-
Knight, A. T. Pain 2001, 93, 191–196; (h) Bialer, M.;
Johannessen, S. I.; Kupferberg, H. J.; Levy, R. H.;
Loiseau, P.; Perucca, E. Epilepsy Res. 2002, 51, 31–71; (i)
Kasper, S.; Blagden, M.; Seghers, S.; Veerman, A.; Volz,
H. P.; Geniaux, A.; Strub, N.; Marchand, A.;
Maisonobe, P.; Mikkelsen, H. Eur. Neuropsychopharm.
2002, 12, 341–342.
3.11. (3R,4R,1%S)-4-Benzyloxymethyl-3-(2%%-methylprop-
1%%-yl)-1-(1%-phenylethyl)pyrrolidine, 14
This product was prepared in 77% yield as a colourless
oil from 13 by the method described for compound 7.
1H NMR: 0.82 (d, 6H, J=6.4), 1.21–1.32 (m, 1H), 1.34
(d, 3H, J=6.6), 1.36–1.54 (m, 1H), 1.65–1.85 (m, 1H),
1.91–2.08 (m, 2H), 2.42–2.56 (m, 1H), 2.63 (dd, 1H,
J=7.5, J=9.4), 2.69 (dd, 1H, J=4.8, J=9.4), 3.14 (q,
1H, J=6.6), 3.39–3.48 (m, 2H), 4.52 (s, 2H), 7.16–7.41
(m, 10 ArH); 13C NMR: 22.9, 23.7, 23.8, 27.0, 39.2,
45.3, 56.7, 60.0, 66.1, 73.5, 74.4, 127.2, 127.7, 128.0,
128.1, 128.7, 128.8, 139.2, 146.4; [h]D +10.1 (c 1,
CHCl3); MS (EI): m/z 352 (M++1), 336, 309, 204, 105,
91. Anal. calcd for C24H33NO: C, 82.00; H, 9.46; N,
3.98. Found: C, 81.95; H, 9.40; N, 4.01.
3.12. (3R,4R)-3-Benzyloxymethyl-1-(t-butoxycarbonyl)-
4-(2%-methylprop-1%-yl)pyrrolidine, ent-8
2. Ling, R.; Ekhato, I. V.; Rubin, J. R.; Wustrow, D. J.
Tetrahedron 2001, 57, 6579–6588.
3. (a) Denes, F.; Chemla, F.; Normant, J. F. Synlett 2002,
919–922; (b) Dong, J.; Kou, B.; Li, R.; Cheng, T. Synth.
Commun. 2002, 32, 935–939.
This product was prepared in 79% yield from 14 by the
method described for compound 8. [h]D +26.8 (c 0.5,
CHCl3).
4. Fava, C.; Galeazzi, R.; Mobbili, G.; Orena, M. Hetero-
cycles 1999, 51, 2463–2468.
3.13. (3R,4R)-1-(t-Butoxycarbonyl)-3-hydroxymethyl-4-
(2%-methylprop-1%-yl)pyrrolidine, ent-9
5. (a) Cardillo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.
Synlett 1995, 1159–1160; (b) Galeazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron 1996, 52, 1069–1084; (c) Galeazzi,
R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 79–88.
6. (a) Meyers, A. I.; Kunnen, K. B.; Still, W. C. J. Am.
Chem. Soc. 1987, 109, 4405–4407; (b) Matsuo, J.;
Kobayashi, S.; Koga, K. Tetrahedron Lett. 1998, 39,
9723–9726.
This product was prepared in 80% yield from ent-8 by
the method described for compound 9. [h]D +35.8 (c
4.6, CHCl3).
3.14. Methyl (3R,4R)-1-t-butoxycarbonyl-4-(2%-methyl-
prop-1%-yl)-3-pyrrolidinecarboxylate, ent-10
7. The alkylation of g-lactams was generally carried out by
first protecting the nitrogen atom with a carbamate. See,
for example: (a) Baldwin, J. E.; Miranda, T.; Moloney,
M. Tetrahedron 1989, 45, 7459–7468; (b) Hagen, T. J.
This product was prepared in 78% yield from ent-9 by
the method described for compound 10. [h]D +37.5 (c
2.0, MeOH).

3358
R. Galeazzi et al. / Tetrahedron: Asymmetry 14 (2003) 3353–3358
9. Rao, V. S.; Perlin, A. S. Carbohydr. Res. 1980, 83,
Synlett 1990, 63–66; (c) Ezquerra, J.; Pedregal, C.; Rubio,
175–178.
A.; Yruretagoyena, B.; Escribano, A.; Sanchez-Ferrando
F. Tetrahedron 1993, 49, 8665–8678; (d) Maldaner, A. O.;
Pilli, R. A. Tetrahedron 1999, 55, 13321–13332.
10. Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J.
J. Chem. Soc. 1953, 2548–2552.
11. Cainelli, G.; Manescalchi, F. Synthesis 1975, 723–724.
8. Jang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195–196.