A stereoselective approach to both 3,4-trans-disubstituted pyrrolidin-2-ones and pyrrolidines. A convenient synthesis of (3R,4R)-4-benzyl-3-pyrrolidinecarboxylic acid

Article abstract of DOI:10.3987/com-03-9854

Chiral 4-alkyloxymethyl- and silyloxymethylpyrrolidin-2-ones, (10a-c), underwent alkylation to give the corresponding 3,4-trans-disubstituted pyrrolidin-2-ones, (11a-g), in good yield and total stereoselection, as shown by ¹H NMR spectral data

Full text of DOI:10.3987/com-03-9854

HETEROCYCLES, Vol. 60, No. 11, 2003, pp. 2485 - 2498
Received, 10th July, 2003, Accepted, 10th September, 2003, Published online, 16th September, 2003
A
STEREOSELECTIVE
3,4-TRANS-DISUBSTITUTED
PYRROLIDINES.
(3R,4R)-4-BENZYL-3-PYRROLIDINECARBOXYLIC ACID
APPROACH
PYRROLIDIN-2-ONES
CONVENIENT SYNTHESIS
TO
BOTH
AND
OF
A
Roberta Galeazzi, Gianluca Martelli, Giovanna Mobbili, Mario Orena,* and
Maria Panagiotaki
Dipartimento di Scienze dei Materiali e della Terra - Università Politecnica delle
Marche, Via Brecce Bianche - I-60131 Ancona, Italy, orena@mta01.unian.it
Abstract – Chiral 4-alkyloxymethyl- and silyloxymethylpyrrolidin-2-ones,
(10a-c), underwent alkylation to give the corresponding 3,4-trans-disubstituted
pyrrolidin-2-ones, (11a-g), in good yield and total stereoselection, as shown by
1H NMR spectral data and n.O.e. experiments. Moreover compounds (11a-c)
were converted into the corresponding 3,4-trans-disubstituted pyrrolidines,
(12a-c). Removal of the chiral auxiliary from 12a, followed by protection of the
nitrogen with t-Boc group, led to the corresponding derivative (13). Cleavage of
the benzyl ether and subsequent oxidation of the hydroxy function afforded
(3R,4R)-4-benzyl-3-pyrrolidinecarboxylic acid (4).
INTRODUCTION
Chiral 3,4-trans-disubstituted pyrrolidin-2-ones and pyrrolidines were shown to exhibit a broad spectrum
1
of pharmacological activities. Thus, pilolactam (1) is effective in oftalmology, compound Sch 50971,
(2), acts as H3 agonist, 2 the amide (3) showed an interesting dopamine receptor binding activity 3 and an
analogue of the endogeneous peptide PLG (Pro-Leu-Gly-NH2) in which Pro is changed with
trans-4-benzyl-3-pyrrolidinecarboxylic acid, (4), resulted metabolically more stable than the parent
4
tripeptide in treatment of both the Parkinson disease and schizofrenia (Scheme 1). In addition, several
enantiopure 1,3,4-substituted pyrrolidines were prepared and used as auxiliaries for a lot of important

5
transformations.
Therefore, the development of methods for the stereoselective synthesis of
3,4-disubstituted pyrrolidin-2-ones, which can be precursors of 3,4-disubstituted pyrrolidines, is of
growing interest. 6,7
Me
N
O
Cl
N
H
N
N
MeO
NHMe
O
N
H
Bn
1
2
N
COOH
N
H
N
H
N
H
3
4
Scheme 1
RESULTS AND DISCUSSION
Within a project directed towards the synthesis of conformationally restricted non proteinogenic amino
8
acids active at the CNS level,
we devised that enantiomerically pure 4,5-trans-disubstituted
pyrrolidin-2-ones could arise from pyrrolidin-2-ones (6) and (7) we already obtained by cyclisation of the
chiral malonamide (5) mediated by Mn(III) (Scheme 2). 8c
MeOOC
MeOOC
MeOOC
ref. 8a
+
O
O
O
N
N
N
5
6
7
Ph
Ph
Ph
Scheme 2
Thus, pyrrolidin-2-one (6) was easily converted into the corresponding 4-hydroxymethyl derivative (8), 8c
but alkylation carried out with n-BuLi in THF, followed by addition of the appropriate alkyl halide,
proceeded in low yield, to give 9, probably due to the low solubility of the dianion. On the other hand,

when HMPA was employed in order to completely dissolve the dianion, substantial amounts of the
O-alkylation product were isolated from the reaction mixture (Scheme 3).
R
OH
OH
i
ii
6
O
O
N
N
9
8
Ph
Ph
Scheme 3. Reagents and conditions: i. See ref. 9. ii. n-BuLi (2 equiv), THF, HMPA, 0°C (a. R =
C6H5CH2, 51%; b. R = C2H5, 48%; c. R = C6H5CH2OCH2, 44%).
However, when 4-hydroxymethyl derivative (8) was converted into the corresponding benzyl,
tetrahydropyranyl or TBDMS ethers (10) respectively, the alkylation proceeded in high yield and total
stereoselection to give 3,4-disubstituted pyrrolidin-2-ones (11), the trans-isomer being the sole product
isolated from the reaction mixture, whose configuration was assigned on the basis of n.O.e. experiments
(Scheme 4). The stereochemical outcome of the reaction leading to 3,4-trans-disubstituted compounds
(11), exclusively, can be ascribed to the effect of the substituent at C-4. In fact, by steric hindrance the
alkylating reagent is biased to attack the enolate anion of 10 only from the opposite side with respect to this
substituent.
n.O.e. 6-8%
CH3
O
OR1
H
H
ii
i
N
8
O
N
R2
OR1
10
H
Ph
11
Scheme 4. Reagents and conditions. i. For 10a (R1 = Bn): n-BuLi, THF, HMPA, then BnBr, 91%. For
10b (R1 = THP): H 15, DHP, DCM, 81%. For 10c (R1 =TBDMS): NaH, THF, then TBDMSCl, 78%. ii.
n-BuLi, THF, 0°C. a. R1 = R2 = Bn, 87%; b. R1 = Bn, R2 = Et, 91%; c. R1 = Bn, R2 = BnOCH2, 67% ; d.
R1 = THP, R2 = BnOCH2, 71%; e. R1 = THP, R2 = COOMe, 68%; f. R1 = THP, R2 = t-BuCOOCH2, 66%;
g. R1 = TBDMS, R2 = n-Pr, 85%.
Since the reduction of pyrrolidin-2-ones to the corresponding pyrrolidines is of interest in both natural
7
products and synthetic chemistry, the pyrrolidin-2-ones (11a-c) were converted into the corresponding

pyrrolidines (12a-c) by treatment with LAH in refluxing THF (Scheme 5).
R
R
OBn
11
OBn
12
i
O
N
N
Ph
Ph
Scheme 5. Reagents and conditions. i. LAH, refluxing THF. a. R = Bn, 78%; b. R = Et, 76%; c. R =
BnOCH2, 78%.
The usefulness of this approach to chiral 3,4-trans-disubstituted pyrrolidines was proven by the synthesis
of the bioactive non proteinogenic amino acid (3R,4R)-(4).4 Thus, starting from 12a, the chiral phenylethyl
10
group was removed by using chloroethyl chloroformate in methanol,
to give the corresponding
pyrrolidine which was directly converted into the corresponding t-Boc derivative (13). The cleavage of
the benzyl ether, performed by catalytic transfer hydrogenation in HCOOH, 11 gave the alcohol (14), and
subsequent oxidation, carried out by using the Jones’ reagent at low temperature, led to the carboxylic acid,
which without isolation was converted into its methyl ester (15) by using CH2N2. Eventually, removal of
both the t-Boc and the methyl ester groups, carried out by treating with aqueous HCl, followed by elution
on Dowex 50WX2, allowed to obtain the (3R,4R)-4-benzyl-3-pyrrolidinecarboxylic acid (4) (Scheme 6). 13
Bn
Bn
OBn
OH
i
ii
12a
N
N
13
14
t-Boc
t-Boc
Bn
COOMe
Bn
COOH
iv
iii
N
N
H
15
4
t-Boc
Scheme 6. Reagents and conditions: i. MeCH(Cl)OCOCl, refluxing DCM, refluxing MeOH, then
Boc2O, Et3N, DMAP, DCM, 71% yield. ii. 10% Pd-C, HCOOH, EtOH, 82% yield. iii. Jones’ reagent,
then CH2N2, 83% yield. iv. a. 3 M HCl, rt,. b. Dowex 50WX2, 1 M NH4OH as eluant, 50% overall yield.

EXPERIMENTAL
IR spectra were recorded on FT-IR Fourier Nicolet 20-SX spectrophotometer. 1H and 13C NMR spectra
were determined on a Varian Gemini 200 spectrometer at 200 and 50.3 MHz for 1H and 13C, respectively,
in CDCl3 unless otherwise reported. Chemical shifts are given as ppm from tetramethylsilane and J values
are given in Hz. Diastereomeric purity was determined by g.l.c. analysis by using a Chrompack 9001
gas-chromatograph equipped with a capillary column Chrompack 7720 (50 m x 0.25 mm i.d.; stationary
phase CP-Sil-5 CB). Optical rotations, [α]D, were recorded at room temperature on a Perkin-Elmer Model
241 polarimeter at the sodium D line (concentration in g/100 mL). MS spectral 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 atmosphere. Compound (8) was obtained according ref. 9.
General procedure for the alkylation of pyrrolidin-2-one (8).
To a solution of pyrrolidin-2-one (8) (2.2 g; 10 mmol) in dry THF (30 mL) n-BuLi ( 2.5 M in hexanes; 8
mL; 20 mmol) was added under argon at -15 °C and the mixture was stirred for 20 min. Then a solution
of the appropriate halide (10 mmol) dissolved in dry THF (10 mL) was added. After 1 h H2O (100 mL)
was added and the mixture extracted with ethyl acetate (3 x 100 mL). After drying (Na2SO4) the solvent
was removed under reduced pressure and the residue was purified by silica gel chromatography
(cyclohexane:ethyl acetate 70:30) to give pure compounds (9a-c).
(3R,4R,1’R)-3-Benzyl-4-hydroxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (9a)
Starting from 8 and benzyl bromide, 9a (1.6 g; 51% yield) was obtained as a colorless oil. IR (CHCl3):
3350, 1665 cm-1; 1H NMR: 1.50 (d, 3H, J = 7.1), 1.71 (br s, 1H, OH), 2.13 (m, 1H), 2.62 (ddd, 1H, J = 4.6,
J = 7.6, J = 8.0), 2.75 - 2.93 (m, 2H), 3.06 (dd, 1H, J = 6.6, J =13.7), 3.17 (dd, 1H, J = 4.5, J = 13.7), 3.32
(dd, 1H, J = 7.2, J = 10.5), 3.41 (dd, 1H, J = 5.3, J = 10.5), 5.48 (q, 1H, J = 7.1), 7.14 - 7.38 (m, 10 ArH);
13C NMR: 16.6, 36.5, 36.9, 44.2, 46.7, 49.6, 64.2, 126.9, 127.0, 127.5, 127.6, 127.8, 128.0, 128.1, 129.0,
129.8, 129.9, 139.3, 140.4, 175.3; [α]D +73.7° (c 0.5, 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, 77.59; H, 7.45; N, 4.58.
(3R,4R,1’R)-3-Ethyl-4-hydroxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (9b)
Starting from 8 and ethyl iodide, 9b (1.2 g; 48% yield) was obtained as a colorless oil. IR (CHCl3): 3345,
1668 cm-1; 1H NMR: 0.94 (t, 3H, J = 7.3), 1.50 (d, 3H, J = 7.1), 1.54 - 1.86 (m, 2H), 2.04 (br s, 1H, OH),
2.11 - 2.31 (m, 2H), 3.02 (dd, 1H, J = 7.9, J = 9.8), 3.13 (dd, 1H, J = 5.8, J = 9.8), 3.55 (dd, 1H, J = 7.2, J
= 10.4), 3.69 (dd, 1H, J = 4.9, J = 10.4), 5.47 (q, 1H, J = 7.1), 7.21 - 7.42 (m, 5 ArH); 13C NMR: 11.5, 16.5,

23.9, 39.1, 44.3, 46.4, 49.3, 65.1, 127.5, 127.6, 127.9, 129.0, 140.6, 176.0; [α]D +68.4° (c 0.5, CHCl3); MS
(EI): m/z 247 (M+), 232, 105, 91, 77. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.79; H, 8.52; N, 6.39.
(3R,4R,1’R)-3-Benzyloxymethyl-4-hydroxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (9c)
Starting from 8 and benzyl chloromethyl ether, 9c (1.5 g; 43% yield) was obtained as a colorless oil. IR
(CHCl3): 3345, 1670 cm-1; 1H NMR: 1.51 (d, 3H, J = 7.1), 2.25 - 2.47 (m, 1H), 2.62 (ddd, 1H, J = 11.7, J
= 8.3,
J
= 3.5), 2.95 (dd, 1H,
J
= 7.8,
J
= 9.6), 3.06 (dd, 1H,
J = 8.7, J = 9.6), 3.32 (br s, 1H, OH), 3.55 - 3.69
(m, 3H), 3.96 (dd, 1H,
J
= 9.2,
J
= 3.5), 5.47 (q, 1H, J
= 7.1), 7.19 - 7.41 (m, 10 ArH); 13C NMR: 16.6, 40.8,
43.6, 48.5, 49.6, 65.1, 70.9, 74.1, 127.4, 127.9, 128.3, 128.4, 128.9, 129.0, 129.1, 137.9, 140.3, 173.1; [α]D
+85.9° (c 1, CHCl3); MS (EI): m/z 339 (M+), 324, 233, 202, 188, 172, 105, 91, 77. Anal. Calcd for
C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.25; H, 7.36; N, 4.08.
(4R,1’R)-4-Benzyloxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (10a)
To a solution containing pyrrolidin-2-one (8) (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 x 100 mL). After
drying (Na2SO4), the solvent was removed under reduced pressure and the residue was purified by silica
gel chromatography (cyclohexane:ethyl acetate 50:50) to give 10a (2.8 g; 91% yield) as a colorless oil. IR
(CHCl3): 3347, 1665 cm-1; 1H NMR: 1.48 (d, 3H, J = 7.0), 2.16 - 2.32 (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; [α]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.
(4R,1’R)-1-Phenylethyl-4-tetrahydropyranyloxymethylpyrrolidin-2-one (10b).
To a solution containing the pyrrolidin-2-one (8) (2.2 g; 10 mmol) and dihydropyran (1.68 g; 20 mmol) in
ethyl acetate (50 mL) resin 15 (3.0 g) was added and the mixture was stirred for 3 h at 0 °C. Then the resin
was filtered off, the solvent removed under reduced pressure and the residue purified by silica gel
chromatography (cyclohexane:ethyl acetate 30:70) to give 10b (2.5 g; 81% yield) as a colorless oil
(equimolar diastereomeric mixture). IR (CHCl3): 1665 cm-1; 1H NMR: 1.52 (d, 3H, J = 7.1), 1.53 - 1.96 (m,
6H), 2.18 - 2.38 (m, 1H), 2.42 - 2.64 (m, 2H), 3.01 - 3.22 (m, 2H), 3.24 - 3.41 (m, 1H), 3.43 - 3.56 (m, 1H,

3.63 - 3.86 (m, 2H), 4.57 (m, 1H), 5.49 (q, 1H, J
= 7.1), 7.22 - 7.41 (m, 5 ArH); 13C NMR: 16.5, 19.9, 25.8,
30.9, 31.6 (50%), 31.7 (50%), 35.2, 45.8 (50%), 45.9 (50%), 49.3, 62.8, 69.9, 99.4 (50%), 99.6 (50%),
127.5, 127.9, 129.0, 140.5, 173.8 (50%), 173.9 (50%). Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N,
4.62. Found: C, 71.19; H, 8.27; N, 4.59.
(4R,1’R)-4-t-Butyldimethylsilyloxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (10c)
In a three-necked flask under argon atmosphere NaH (480 mg; 50% in mineral oil; 10 mmol) was
suspended in pentane (20 mL) under stirring and after 10 min the solvent was removed by decanting. Then
dry THF (30 mL) was added, followed by a solution of compound (8) (2.2 g; 10 mmol) dissolved in dry
THF (15 mL). After 15 min a solution containing TBDMSCl (1.5 g; 10 mmol) in dry THF (5 mL) was
added at 0 °C and the reaction mixture was stirred at rt for 6 h. The clear solution was poured in H2O-ice
and extracted with ethyl acetate (3 x 50 mL). After drying (Na2SO4), the solvent was removed under
reduced pressure and the residue was purified by silica gel chromatography (cyclohexane:ethyl acetate
70:30) to give 10c (2.6 g; 78% yield) as a colorless oil. IR (CHCl3): 1667 cm-1; 1H NMR: 0.03 (s, 6H), 0.86
(s, 9H), 1.51 (d, 3H, J = 7.2), 2.19 - 2.54 (m, 3H), 3.01 (dd, 1H, J = 7.9, J = 9.7), 3.16 (dd, 1H, J = 3.7, J =
9.7), 3.50 (dd, 1H, J = 6.1, J = 10.1), 3.56 (dd, 1H, J = 5.1, J = 10.1), 5.49 (q, 1H, J = 7.2), 7.21 - 7.39 (m,
13
5 ArH); C NMR: -5.0, -4.9, 16.6, 18.7, 26.3, 33.7, 34.7, 45.1, 49.3, 65.1, 127.6, 127.9, 129.0, 140.7,
174.0; [α]D +55.7° (c 5, CHCl3); MS (EI): m/z 333 (M+), 318, 214, 105, 77, 57. Anal. Calcd for
C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20. Found: C, 69.38; H, 9.41; N, 4.17.
General procedure for the alkylation of pyrrolidin-2-ones (10a-c).
To a solution of pyrrolidin-2-ones (10a-c) (10 mmol) in dry THF (30 mL), n-BuLi (2.5 M solution in
hexanes; 4.0 mL; 10 mmol) was added dropwise at - 15 °C under argon atmosphere. After stirring for 20
min, a solution of the appropriate halide (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 x 100 mL). The organic layer was washed with water, dried (Na2SO4) and
evaporated. The crude oil was purified by silica gel chromatography (cyclohexane:ethyl acetate 50:50) to
give the pure pyrrolidin-2-ones (11a-g).
(3R,4R,1’R)-3-Benzyl-4-benzyloxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (11a)
Starting from 10a and benzyl bromide, 11a (3.1 g; 78% yield) was obtained as a colorless oil. IR (CHCl3):
1664 cm-1; 1H NMR: 1.48 (d, 3H, J = 7.0), 2.15 - 2.35 (m, 1H), 2.67 (ddd, 1H, J = 4.6, J = 7.5, J = 12.2),
4.37 (ABq, 2H, J = 12.4), 5.51 (q, 1H, J = 7.0), 7.13 - 7.43 (m, 15 ArH); 13C NMR: 16.6, 35.6, 37.1, 44.5,
46.9, 49.4, 71.8, 73.6, 126.9, 127.4, 127.8, 128.1, 128.2, 128.9, 129.9, 138.5, 139.3, 140.6, 175.0; [α]D

+34.2° (c 1, CHCl3); MS (EI): m/z 399 (M+), 384, 307, 158, 77. Anal. Calcd for C27H29NO2: C, 81.17; H,
7.32; N, 3.51. Found: C, 81.11; H, 7.28; N, 3.47.
(3R,4R,1’R)-4-Benzyloxymethyl-3-ethyl-1-(1’-phenylethyl)pyrrolidin-2-one (11b)
Starting from 10a and ethyl iodide, 11b (2.6 g; 76% yield) was obtained as a colorless oil. IR (CHCl3):
1660 cm-1; 1H NMR: 0.96 (t, 3H, J = 7.0), 1.49 (d, 3H, J = 7.1), 1.51 - 1.75 (m, 2H), 2.16 - 2.32 (m, 2H),
3.10 (dd, 1H, J = 7.9, J = 9.9), 3.09 (dd, 1H, J = 6.1, J = 9.9), 3.38 (dd, 1H, J = 7.5, J = 9.1), 3.51 (dd, 1H,
J = 4.7, J = 9.1), 4.50 (ABq, 2H, J = 12.2), 5.49 (q, 1H, J = 7.1), 7.21 - 7.34 (m, 10 ArH); 13C NMR: 11.5,
16.4, 23.8, 27.4, 37.2, 44.6, 46.7, 49.2, 72.6, 73.7, 127.5, 127.8, 128.1, 128.2, 128.9, 138.5, 140.8, 175.8;
[α]D +98.9° (c 1, CHCl3); MS (EI): m/z 337 (M+), 322, 158, 77. Anal. Calcd for C22H27NO2: C, 78.30, H,
8.06; N, 4.15. Found: C, 78.24; H, 8.01; N, 4.11.
(3R,4R,1’R)-3,4-Dibenzyloxymethyl-1-(1’-phenylethyl)pyrrolidin-2-one (11c)
Starting from 10a and chloromethyl benzyl ether, 11c (2.9 g; 67%) was obtained as a colorless oil. IR
(CHCl3): 1660 cm-1; 1H NMR: 1.54 (d, 3H,
= 6.9, = 9.1), 3.57 (dd, 1H, = 5.0, = 9.1), 3.76 (dd, 1H,
J
= 7.1), 2.55 - 2.75 (m, 2H), 3.07 - 3.21 (m, 2H), 3.46 (dd, 1H,
J
J
J
J
J
= 3.2, = 9.4), 3.90 (dd, 1H, = 4.0, = 9.4),
J
J
J
4.55 (ABq, 2 x 2H, J = 12.5), 5.55 (q, 1H, J = 7.1), 7.11 - 7.45 (m, 15 ArH); 13C NMR: 16.7, 35.7, 44.8,
46.8, 49.4, 70.2, 72.3, 73.7, 73.8, 127.3, 127.4, 127.5, 127.6, 127.7, 127.9, 128.1, 128.2, 128.4, 128.5,
128.7, 128.8, 128.9, 138.5, 138.9, 140.5, 173.8; [α
]D +80.5° (c 1, CHCl3); MS (EI): m/z 429 (M+) 414, 352,
338, 214, 157, 91, 77. Anal. Calcd for C28H31NO3: C, 78.29; H, 7.27; N, 3.26. Found: C, 78.23; H, 7.24; N,
3.22.
(3R,4R,1’R)-3-Benzyloxymethyl-1-phenylethyl-4-tetrahydropyranyloxymethylpyrrolidin-2-one
(11d)
Starting from 10b and chloromethyl benzyl ether, 11d (3.0 g; 71%) was obtained as a colorless oil
(equimolar diastereomeric mixture). IR (CHCl3): 1665 cm-1; 1H NMR: 1.44 - 1.81 (m, 6H), 1.55 (d, 3H, J
= 7.2), 2.35 - 2.64 (m, 2H), 2.91 - 3.21 (m, 3H), 3.28 - 3.54 (m, 3H), 3.58 - 3.91 (m, 4H), 4.51 (ABq, 2H,
J
= 12.5), 4.56 (m, 1H), 5.54 (q, 1H,
J
= 7.2), 7.15 - 7.42 (m, 10 ArH); 13C NMR: 16.5, 19.9, 25.8, 30.9, 31.6
(50%), 31.7 (50%), 35.2, 45.8 (50%), 45.9 (50%), 49.3, 62.8, 69.9, 99.4 (50%), 99.6 (50%),127.5, 127.9,
129.0, 140.5,173.8 (50%), 173.9 (50%). Anal. Calcd for C26H33NO4: C, 73.73; H, 7.65; N, 3.31. Found: C.
73.66; H, 7.59; N, 3.26.
(3R,4R,1’R)-3-Methoxycarbonyl-1-phenylethyl-4-tetrahydropyranyloxymethylpyrrolidin-2-one
(11e)

Starting from 10b and methyl chloroformate, 11e was obtained (2.4 g; 68%) as a colorless oil (equimolar
diastereomeric mixture). IR (CHCl3): 1665 cm-1; 1H NMR: 1.41 - 1.88 (m, 6H), 1.53 (d, 3H, J = 7.1), 2.75
- 3.01 (m, 1H), 3.06 - 3.22 (m, 2H), 3.31 - 3,59 (m, 3H), 3.65 - 3.90 (m, 2H), 3.78 (s, 3H), 4.57 (m, 1H),
5.45 (q, 1H, J = 7.1); 13C NMR: 16.4 (50%), 16.6 (50%), 19.7, 25.8, 30.8, 36.5 (50%), 36.6 (50%), 44.2
(50%), 44.4 (50%), 49.9, 52.7 (50%), 53.1 (50%), 62.6 (50%), 62.7 (50%), 68.1 (50%), 68.4 (50%), 78.2,
99.3 (50%), 99.6 (50%), 127.4, 127.8, 128.0, 129.1, 140.0, 169.2. Anal. Calcd for C20H20NO5: C, 67.79; H,
5.69; N, 3.95. Found: C, 67.83; H, 5.62; N, 3.91.
(3R,4R,1’R)-1-(1’-Phenylethyl)-3-pivaloyloxymethyl-4-tetrahydropyranyloxymethylpyrrolidin-2-
one (11f)
Starting from 10b and chloromethyl pivalate, 11f was obtained (2.6 g; 66%) as a colorless oil (equimolar
diastereomeric mixture). IR (CHCl3): 1736, 1668 cm-1; 1H NMR: 1.28 (s, 9H), 1.35 - 1.91 (m, 6H), 1.51 (d,
3H, J = 7.1), 2.59 - 2.78 (m, 1H), 2.96 - 3.10 (m, 1H), 3.12 - 3.35 (m, 3H), 3.41 - 3.56 (m, 1H), 3.62 - 3.74
(m, 3H), 4.05 (dd, 1H, J = 4.9, J = 8,9), 4.56 (m, 1H), 5.41 (q, 1H, J = 7.1), 7.18 - 7.41 (m, 5 ArH); 13C
NMR: 16.7, 19.8 (50%), 20.0 (50%), 25.8, 26.2, 26.3, 30.9, 37.5 (50%), 37.6 (50%), 44.6 (50%), 44.8
(50%), 45.6, 49.6, 53.2 (50%), 53.6 (50%), 62.8 (50%), 63.0 (50%), 68.4 (50%), 68.9 (50%), 99.5 (50%),
99.6 (50%); 127.4, 127.9, 129.0,140.0 (50%), 140.1 (50%), 171.0 (50%), 171.1 (50%). Anal. Calcd for
C23H33NO5: C, 68.46; H, 8.24; N, 3.47. Found: C, 68.39; H, 8.19; N, 3.43.
(3R,4R,1’R)-4-t-Butyldimethylsilyloxymethyl-1-(1’-phenylethyl)-3-propylpyrrolidin-2-one (11g)
Starting from 10c and propyl iodide, 11g (3.3 g; 87%) was obtained as a colorless oil. IR (CHCl3): 1667
cm-1; 1H NMR: 0.01 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9H), 0.89 (t, 3H, J = 6.9), 1.28 - 1.51 (m, 3H), 1.48 (d,
3H, J = 7.0), 1.61 - 1.81 (m, 1H), 1.99 - 2.14 (m, 1H), 2.22 - 2.34 (m, 1H), 2.92 (dd, 1H, J = 8.1, J = 9.8),
3.06 (dd, 1H, J = 5.7, J = 9.8), 3.50 (dd, 1H, J = 6.4, J = 10.0), 3.57 (dd, 1H, J = 5.2, J = 10.0), 5.48 (q, 1H,
J = 7.0), 7.18 - 7.34 (m, 5 ArH); 13C NMR: -5.2, -5.1, 14.4, 16.2, 18.4, 20.3, 26.1, 27.2, 33.2, 39.6, 43.3,
44.5, 48.9, 64.6, 127.1, 127.5, 128.7, 140.6, 175.8; [α]D +100.4° (c 5, CHCl3); MS (EI): m/z 376 (M+ + 1),
360, 318, 214, 188, 105, 91, 77, 57. Anal. Calcd for C22H37NO2Si: C, 70.35, H, 9.93; N, 3.73. Found: C,
70.29; H, 9.89; N, 3.76.
General procedure for preparation of pyrrolidines (12a-c).
To a solution containing pyrrolidin-2-ones (11a-c) (10 mmol) in dry THF (40 mL), LiAlH4 (0.78 g; 20
mmol) was added under inert atmosphere and the mixture was refluxed for 3 h. Then MeOH (5 mL) and
aqueous saturated NH4Cl solution(30 mL) were subsequently added and the mixture was extracted with
ethyl acetate (3 x 100 mL). After drying (Na2SO4), the solvent was removed under reduced pressure and

the residue was purified by silica gel chromatography (cyclohexane:ethyl acetate 50:50) to give the
pyrrolidines (12a-c) as colorless oils.
(3R,4R,1’R)-3-Benzyl-4-benzyloxymethyl-1-(1’-phenylethyl)pyrrolidine (12a)
Starting from 11a, 12a (3.0 g; 78%) was obtained as a colorless oil. 1H NMR: 1.51 (d, 3H, J = 6.7), 2.15 -
2.38 (m, 2H), 2.47 (dd, 1H,
J
= 6.9,
= 9.9), 3.15 (dd, 1H,
= 12.3), 7.09 - 7.42 (m, 15 ArH); 13C NMR: 23.2, 40.5, 42.2, 43.8, 56.0, 57.9, 65.9, 72.4, 73.5, 126.6,
]D +26.0° (c 1, CHCl3); MS (EI): m/z 386
J
= 9.9), 2.61 - 2.75 (m, 2H), 2.82 (dd, 1H,
J
= 6.1,
J
= 13.5), 2.99 (dd,
1H,
2H,
J
J
= 6.7,
J
J
= 7.6, = 9.9), 3.28 (d, 2H, = 5.5), 3.58 (q, 1H,
J
J
J = 6.7), 4.40 (ABq,
128.1, 128.2, 128.4, 128.9, 129.1, 129.3, 138.8, 140.7, 141.9; [
α
(M+ +1), 371, 370, 279, 188, 107, 91, 77. Anal. Calcd for C27H31NO: C, 84.11; H, 8.10; N, 3.63. Found: C,
84.05; H, 8.04; N, 3.58.
(3R,4R,1’R)-4-Benzyloxymethyl-3-ethyl-1-(1’-phenylethyl)pyrrolidine (12b)
Starting from 11b
3H, J = 6.6), 1.41 - 1.58 (m, 2H), 1.60 - 1.78 (m, 1H), 1.95 - 2.12 (m, 2H), 2.40 (dd, 1H, J = 4.8, J = 9.2),
2.58 (dd, 1H, = 9.2, = 9.2), 2.92 (dd, 1H, = 8.0, = 8.0), 3.17 (q, 1H, = 7.3), 3.38 (dd, 1H, = 8.8,
= 9.0), 3.44 (dd, 1H, = 6.1, =9.0), 4.50 (ABq, 2H,
= 12.1), 7.18 - 7.45 (m, 10 ArH); 13C NMR: 13.1,
, J = 7.3), 1.37 (d,
12b (2.5 g; 76%) was obtained as a colorless oil. 1H NMR: 0.88 (t, 3H,
J
J
J
J
J
J
J
J
J
J
23.8, 28.4, 43.3, 44.4, 57.2, 59.3, 66.2, 73.5, 74.5, 127.2, 127.6, 127.9, 128.0, 128.7, 128.8, 139.1; [α]D
+36.3° (c 0.9, CHCl3); MS (EI): m/z 324 (M+ +1), 309, 308, 232, 203, 188, 105, 91, 77. Anal. Calcd for
C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.61; H, 8.98; N, 4.29.
(3R,4R,1’R)-3,4-Dibenzyloxymethyl-1-(1’-phenylethyl)pyrrolidine (12c)
Starting from 11c, 12c (3.2 g; 78%) was obtained as a colorless oil. 1H NMR: 1.37 (d, 3H, J = 6.4), 2.04 -
2.25 (m, 2H), 2.31 (dd, 2H,
J
= 5.1,
J
= 9.1), 2.76 (dd, 2H,
J
= 7.2,
J
= 9.1), 3.19 (q, 1H,
J = 6.4), 3.42 (dd,
2H, = 8.8, = 8.9), 3.50 (dd, 2H,
J
J
J
= 5.8, = 8.9), 4.51 (ABq, 4H, J
J
= 12.4), 7.18 - 7.43 (m, 15 ArH); 13C
NMR: 23.7, 41.7, 56.8, 66.0, 73.5, 74.1, 127.3, 127.6, 127.9, 128.7, 128.0, 139.1; [α]D +37.6° (c 0.5,
CHCl3); MS: m/z 416 (M+ +1), 400, 309, 294, 203, 158, 91, 77. Anal. Calcd for C28H33NO2: C, 80.93; H,
8.00; N, 3.37. Found: C, 80.88; H, 7.94; N, 3.33.
(3R,4R)-4-Benzyl-3-benzyloxymethyl-1-t-butoxycarbonylpyrrolidine (13)
To a solution of 12a (1.9 g; 5 mmol) in dichloromethane (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 presssure and to the residue ethyl acetate (100 mL) and 2 M NaOH (50 mL) were added.

After extraction with ethyl acetate (2 x 100 mL), the organic layer was dried (Na2SO4) and then 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-t-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 x 50 mL). After drying (Na2SO4)
and removal of the solvent under reduced pressure, the residue was purified by silica gel chromatography
1
(cyclohexane:ethyl acetate 70:30) to give 13 (1.4 g; 71%) as a colorless oil. IR (CHCl3): 1708 cm-1; H
NMR: 1.44 (s, 9H), 2.12 - 2.39 (m, 2H), 2.56 (dd, 1H, J = 8.5, J = 13.6), 2.86 (dd, 1H, J = 5.1, J = 13.6),
2.95 - 3.12 (m, 1H), 3.12 - 3.27 (m, 1H), 3.30 - 3.71 (m, 4H), 4.47 (s, 2H), 7.11 - 7.44 (m, 10 ArH); 13C
NMR: 29.0, 39.3, 42.2 (60%), 42.8 (40%), 43.6 (40%), 44.4 (60%), 49.2 (40%), 49.8 (60%), 51.5, 71.5,
73.6, 79.6, 126.7, 128.0, 128.1, 128.9, 129.2, 129.3, 138.7, 140.4, 155.0; [α]D +13.9° (c 1.2, CHCl3); MS
(EI): m/z 381 (M+), 366, 280, 219, 129, 91, 57. Anal. Calcd for C24H31NO3: C, 75.56; H, 8.19; N, 3.67.
Found: C, 75.48; H, 8.09; N, 3.75.
(3R,4R)-4-Benzyl-1-t-butoxycarbonyl-3-hydroxymethylpyrrolidine (14)
To a solution containing compound (13) (2.0 g; 5.3 mmol) and HCOOH (6 mL) in dry ethanol (50 mL)
under argon atmosphere, 10 wt. % Pd on activated carbon (1.3 g) was added and the mixture was stirred
for 1 h at rt. Then the catalyst was filtered off, the organic layer was removed under reduced pressure and
the residue was dissolved in ethyl acetate (50 mL). After washing with an aqueous NaHCO3 saturated
solution (30 mL), the solvent was dried (Na2SO4) and evaporation under reduced pressure gave the
compound (14) (1.3 g; 82%) as an oil which was used without further purification. IR (CHCl3): 1708 cm-1;
1H NMR: 1.44 (s, 9H), 1.66 (br s, 1 H, OH), 2.03 - 2.21 (m, 1H), 2.21 - 2.42 (m, 1H), 2.59 (dd, 1H, J = 8.3,
J = 13.7), 2.84 (dd, 1H, J = 5.9, J = 13.7), 2.95 - 3.29 (m, 2H), 3.31 - 3.73 (m, 4H), 7.11 - 7.36 (m, 5 ArH);
13C NMR: 28.5, 38.8, 41.2 (50%), 41.7 (50%), 45.6 (50%), 46.0 (50%), 48.0 (50%), 48.9 (50%), 50.9,
79.2, 126.2, 128.4, 128.5, 128.6, 128.7, 139.8, 154.6 (50%), 160.7 (50%); [α]D +14.1° (c 4.6, CHCl3); MS
(EI): m/z 291 (M+), 260, 234, 177, 91, 57. Anal. Calcd for C17H25NO3. C, 70.07; H, 8.65; N, 4.81. Found:
70.03; H, 8.68; N, 4.77.
Methyl (3R,4R)-4-Benzyl-1-t-butoxycarbonyl-3-pyrrolidinecarboxylate (15)
To a solution containing compound (14) (1.0 g; 3.4 mmol) in acetone (18 mL), the Jones’ reagent (1.9 mL)
was added at -15 °C and the mixture was stirred for 5 min. Then ethyl acetate (20 mL) and subsequently
saturated aqueous Na2CO3 solution (15 mL) were added at 0 °C. After extraction of the aqueous phase with
ethyl acetate (50 mL), organics were discarded and pH of the aqueous layer raised to 2 by slow addition of
1 M HCl under stirring. Then, extraction with ethyl acetate (2 x 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 treated with an ethereal solution of CH2N2 in ether until nitrogen evolution ceased and
the solvent was evaporated under reduced pressure, to give a residue which was purified by silica gel
chromatography (cyclohexane:acetate 70:30) affording the ester (15) (0.9 g; 83% yield) as a colorless oil.
IR (CHCl3): 1743, 1708 cm-1; 1H NMR: 1.44 (s, 9H), 2.55 - 2.95 (m, 4H), 2.95 - 3.14 (m, 1H), 3.38 - 3.60
(m, 2H), 3.63 (s, 3H), 3.63 - 3.81 (m, 1H), 7.11 - 7.36 (m, 5 ArH); 13C NMR: 27.9, 37.9, 42.5 (60%), 43.1
(40%), 46.9 (40%), 47.7, 48.1 (60%), 50.0, 51.3, 78.8, 125.9, 127.9, 128.2, 128.4, 138.4, 153.5, 172.4; [α]D
+20.4° (c 2.7, CHCl3); MS (EI): m/z 319 (M+), 304, 288, 234, 108, 91, 77. Anal. Calcd for C18H25NO4: C,
67.69; H, 7.89; N, 4.39. Found: 67.63; H, 7.86; N, 4.43.
(3R,4R)-4-Benzyl-3-pyrrolidinecarboxylic acid
(4)
The compound (15) (0.53 g; 1.7 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
1
give the corresponding hydrochloride as a white solid [mp 181-183 °C; H NMR (D2O): 2.78 - 3.21
(m, 5H), 3.39 - 3.72 (m, 3H), 7.21 - 7.46 (m, 5 ArH); 13C NMR (D2O): 40.0, 46.3, 49.9, 50.1, 52.6, 129.9,
131.8, 132.0, 141.4, 178.1; [α]D 8.3 (c 1, H2O)]. This product, dissolved in H2O, was subjected to ion
exchange column (Dowex 50WX2, elution with 1 M NH4OH) to give the corresponding amino acid (4) as
a white solid (0.18 g; 50%), mp 241-243 °C (decomp); 1H NMR (CD3OD): 2.52 - 2.87 (m, 3H), 2.91 - 3.16
(m, 2H), 3.18 - 3.34 (m, 1H), 3.43 - 3.53 (m, 2H), 7.12 - 7.33 (m, 5 ArH); 13C NMR (CD3OD): 39.4, 45.9,
49.6, 50.9, 51.9, 127.9, 130.0, 130.2, 130.3, 140.8, 178.3; [α]D +40.1° (c 1.1, MeOH); MS (CI): m/z 206
(M+ +1), 114, 91, 77. Anal. Calcd for C12H15NO2. C, 70.22; H, 7.37, N, 6.82. Found: 70.14; H, 7.28; N,
6.95.
ACKNOWLEDGEMENTS
We thank M.I.U.R. (Roma, Italy) for financial support within the framework PRIN 2002.
REFERENCES AND NOTES
1.
2.
(a) L.J. Dolby, N.A. Fedorouk, S. Esfandiari, and M.E. Garst, US Pat. 5,675,019 (Chem. Abstr.,
1997, 127, 307539). (b) E. WoldeMussie, G. Ruiz, and J. Chen, Invest. Ophthalmol. Vis. Sci.,
1995, 36, S718. (c) F. Ghelfi, F. Bellesia, L. Forti, G. Ghirardini, R. Grandi, E. Libertini, M.C.
Montemaggi, U.M. Pagnoni, A. Pinetti, L. De Buyck, and A.F. Parsons, Tetrahedron, 1999, 55,
5839.
(a) J.A. Hey, R.Aslanian, D.C. Bolser, R.W. Chapman, R.W. Egan C. Rizzo, R. West, N.-Y. Shih,
X. Fernandez, R.L. McLeod, R. West, and W. Kreutner, Arzneim. -Forsch., 1998, 48, 881. (b)

N.-Y. Shih, R. Aslanian, A.T. Lupo, Jr., S. Orlando, J.J. Piwinski, M.J. Green, A.K. Ganguly, R.
West, S. Tozzi, W. Kreutner, and J.A. Hey, Bioorg. Med. Chem. Lett., 1998, 8, 243. (c) R.Aslanian,
G. Lee, R. V. Iyer, N.-Y. Shih, J. J. Piwinski, R.W. Draper, and A.T. McPhail, Tetrahedron:
Asymmetry, 2000, 11, 3867.
3.
4.
C. Thomas, H. Hubner, and P. Gmeiner, Bioorg. Med. Chem. Lett., 1999, 9, 841.
(a) C. Thomas, U. Ohnmacht, M. Niger, and P. Gmeiner, Bioorg. Med. Chem. Lett., 1998, 8, 2885.
(b) P.W. Baures, A. Pradhan, W.H. Ojala, W.B. Gleason, R.K. Mishra, and R.L. Johnson, Bioorg.
Med. Chem. Lett., 1999, 9, 2349.
5.
6.
(a) D.M Huryn, in Comprehensive Organic Synthesis; ed. by B.M. Trost and I. Fleming, Pergamon,
Oxford, 1991, Vol. 1, pp. 64-71. (b) J. Lin, W.H. Chan, A.W.M. Lee, W.Y. Wong, and P.Q. Huang,
Tetrahedron Lett., 2000, 41, 2949.
(a) A.I. Meyers, K.B. Kunnen, and W.C. Still, J. Am. Chem. Soc., 1987, 109, 4405. (b) T.J. Hagen,
Synlett, 1990, 63. (c) S. E. Denmark and L.R. Marcin, J. Org. Chem., 1995, 60, 3221. (d) D. Enders,
R. Grobner, G. Raabe, and J. Runsink, Synthesis, 1996, 941. (e) J. Matsuo, S. Kobayashi, and K.
Koga, Tetrahedron Lett., 1998, 39, 9723. (f) A.O. Maldaner and R.A. Pilli, Tetrahedron, 1999, 55,
13321. (g) D. Enders, P. Teschner. G. Raabe, and J. Runsink, Eur. J. Org. Chem., 2001, 4463. (h) R.
Ling, I.V. Ekhato, J.R. Rubin, and D.J. Wustrow, Tetrahedron, 2001, 57, 6579. (i) F. Denes, F.
Chemla, and J.F. Normant, Synlett, 2002, 919. (j) J. Dong, B. Kou, R. Li, and T. Cheng, Synth.
Comm., 2002, 32, 935.
7.
8.
A. Numata and T. Ibrika, in 'The Alkaloids'; ed. by A. Brossi, Academic Press. New York, 1987,
Vol. 31, Chapter 6.
(a) B. Cardillo, R. Galeazzi, G. Mobbili, and M. Orena, Synlett, 1995, 1159. (b) R. Galeazzi, G.
Mobbili, and M. Orena, Tetrahedron, 1996, 52, 1069. (c) R. Galeazzi, S. Geremia, G. Mobbili, and
M. Orena, Tetrahedron: Asymmetry, 1996, 7, 79. (d) R. Galeazzi, G. Mobbili, and M. Orena,
Tetrahedron: Asymmetry, 1997, 8, 133. (e) R. Galeazzi, G. Mobbili, and M. Orena, Tetrahedron,
1999, 55, 261. (f) R. Galeazzi, G. Mobbili, and M. Orena, Tetrahedron, 1999, 55, 4029. (g) R.
Galeazzi, S. Geremia, G. Mobbili, and M. Orena, Tetrahedron: Asymmetry, 1999, 10, 587. (h) M.
Ciclosi, C. Fava, R. Galeazzi, M. Orena, and J. Sepulveda-Arques, Tetrahedron Lett., 2002, 58,
2219.
9.
C. Fava, R. Galeazzi, G. Mobbili, and M. Orena, Heterocycles, 1999, 51, 2463.
B.V. Jang, D. O'Rourke, and J. Li, Synlett, 1993, 195.
10.
11.
12.
13.
V.S. Rao and A.S. Perlin, Carbohydr. Res., 1980, 83, 175.
A. Bowers, T.G. Halsall, E.R.H. Jones, and A.J. Lemin, J. Chem. Soc., 1953, 2548.
It is worth mentioning that good results were observed also when the (4S,1’R)-4-hydroxymethyl

derivative (I), easily obtained starting from 7 according ref. 9, was converted into the
corresponding benzyl ether (II) and subsequent alkylation reaction led to IIIa,b in good yield, thus
allowing to prepare the diastereomers of compounds (11). (i. n-Buli, THF, then BnBr, 91% ii.
n-BuLi, THF, 0°C. Then, for IIIa, BnBr, R = Bn, 91% and, for IIIb, EtI, R = Et, 87%).
OH
ref. 9
i
O
7
N
I
Ph
R
OBn
OBn
ii
O
O
N
N
II
III
Ph
Ph