6
G. Veinberg et al. / Bioorg. Med. Chem. xxx (2013) xxx–xxx
for [C12H15NO4+H]+: 238.1077; found: 238.1074. Anal. Calcd for
12H15NO4 (237.26): C, 60.75; H, 6.37; N, 5.90. Found: C, 60.63;
H, 6.29; N 5.78.
7.33 (m, 5H, C6H5); 13C NMR (CDCl3); d = 20.38, 39.36, 49.64,
57.71, 127.22 (C-2, C-6 aromatic), 127.37, 128.82 (C-3, C-5 aro-
matic), 140.85, 176.59; HRMS: calculated for [C11H13NO+Na]+:
198.0895; found: 198.0890.
C
5.1.8. Methyl threo-(3S,4S)-4-nitro-3-phenylpentanoate (3S,4S-
8d)
5.1.13. Ethyl erythro-(4R,5S)-2-(5-methyl-4-phenylpyrrolidin-1-
yl)-acetate (4R,5S-10a)
The factions with Rf 0.26 containing methyl threo-(3S,4S)-4-ni-
tro-3-phenylpentanoate obtained during the chromatographic sep-
aration in Section 5.1.7 were collected and evaporated under
reduced pressure. Yield: 78 mg (13%) of low melting yellow solid.
Optical purity 94% according to chiral HPLC. 1H NMR (CDCl3);
d = 1.27 (d, 3H, J = 6.6 Hz, 5-CH3), 2.58–2.85 (m, 2H, 2-CH2), 3.46
(s, 3 H, OCH3), 3.56–3.71 (m, 1H, 3-H), 4.68–4.77 (m, 1H, 4-H);
7.07–7.31 (m, 5H, C6H5); HRMS: calculated for [C12H15NO4+H]+:
238.1077; found: 238.1073. Anal. Calcd for C12H15NO4 (237.26):
C, 60.75; H, 6.37; N, 5.90. Found: C, 60.60; H, 6.31; N, 5.77.
A solution of erythro-(4R,5S)-5-methyl-4-phenylpyrrolidin-2-
one (4R,5S-9a) (351 mg, 2.00 mM) in toluene (30 ml) was added
to a suspension of sodium hydride (56 mg, 2.35 mM) in toluene
(30 ml). The stirred mixture was heated at 80–90 °C for 30 min
and then cooled to room temperature. Ethyl bromoacetate
(368 mg, 2.20 mM) was added to the reaction mixture, which
was heated to 110–120 °C for 6 h and concentrated under reduced
pressure. The residue was dissolved in toluene (30 ml). The ob-
tained solution was washed with 5% aqueous HCl (2 ꢂ 50 ml),
brine (2 ꢂ 50 ml), dried over anhydrous Na2SO4. The drying re-
agent was removed by filtration, and the solution was concen-
trated under reduced pressure. The residue was purified by silica
column chromatography using CH2Cl2/MeOH (20:1). The fractions
with Rf 0.48 were collected and evaporated under reduced pres-
sure, affording ethyl (4R,5S)-2-(5-methyl-4-phenylpyrrolidin-1-
yl)-acetate (367 mg, 70%) as a colourless oil. 1H NMR (CDCl3);
d = 0.72 (d, 3H, J = 6.6 Hz, 5-CH3), 1.23 (t, 3H, J = 7.0 Hz, CH2CH3),
2.60–2.91 (d, 2H, J = 8.5 Hz, 3-CH2), 3.65–3.74 (m, 1H, 4-H), 3.66
(d, 2H, J = 17.7 Hz, NCH2COO), 4.01–4.10 (m, 1H, 5-H), 4.10–4.20
(m, 2H, CH2CH3), 4.38 (d, 1H, J = 17.7 Hz, NCH2COO), 7.09–7.31
(m, 5H, C6H5); 13C NMR (CDCl3); d = 14.14, 14.62, 35.21, 42.07,
42.29, 57.62, 61.34, 127.14 (C-2, C-6 aromatic), 128.03, 128.51
(C-3, C-5 aromatic), 138.88, 168.89, 174.69; HRMS: calculated for
[C15H29NO3+H]+: 262.1443; found: 262.1433.
5.1.9. erythro-(4R,5S)-5-Methyl-4-phenylpyrrolidin-2-one
(4R,5S-9a)
The hydrogenation was performed using a stirring suspension
of methyl erythro-(3R,4S)-4-nitro-3-phenylpentanoate (3R,4S-8a)
(600 mg, 2.52 mM) in ethanol (40 ml) and 1 ml of 50% Ni Raney
slurry in water at 50 °C and 50 atm for 18 h. After the completion
of the reaction, the reaction mixture was cooled, and the catalyst
was filtered off and washed with 30 ml of ethanol. The filtrate
was concentrated under reduced pressure. The purification of the
residue by column chromatography on silica gel using CH2Cl2/
EtOH (20:1) and collecting fractions with Rf 0.40 afforded ery-
thro-(4R,5S)-5-methyl-4-phenylpyrrolidin-2-one as a white solid.
Yield: 80% (353 mg). 1H NMR (CDCl3); d = 0.75 (d, 3H, J = 6.5 Hz,
5-CH3), 2.55–2.69 (m, 2H, 3-CH2), 3.64–3.72 (m, 1H, 4-H), 3.96–
4.04 (m, 1H, 5-H), 6.78 (br s, 1H, NH), 7.07–7.33 (m, 5H, C6H5);
13C NMR (CDCl3); d = 17.50, 35.22, 44.08, 53.72, 126.51, 127.12,
127.92, 128.50, 128.80, 138.81, 177.84; HRMS: calculated for
[C11H13NO+Na]+: 198.0895; found: 198.0900.
5.1.14. Ethyl threo-(4R,5R)-2-(5-methyl-4-phenylpyrrolidin-1-
yl)-acetate (4R,5R-10b)
The substitution of 4R,5S-9a with 4R,5R-9b in Section 5.1.13
afforded
(4R,5R)-2-(5-methyl-4-phenylpyrrolidin-1-yl)-acetate.
5.1.10. threo-(4R,5R)-5-Methyl-4-phenylpyrrolidin-2-one
(4R,5R-9b)
Yield: 72% (377 mg). 1H NMR (CDCl3 d = 1.16 (d, 3H, J = 6.3 Hz, 5-
CH3), 1.23 (t, 3H, J = 7.0 Hz, CH2CH3), 2.53–2.63 (m, 1H, CH2),
2.76–2.86 (m, 1H, CH2), 2.92–3.01 (m, 1H, 4-H), 3.71 (d, 1H,
J = 17.7 Hz, NCH2COO), 3.74–3.83 (m, 1H, 5-H), 4.10–4.20 (m, 3H,
CH2CH3), 4.38 (d, 1H, J = 17.8 Hz, NCH2COO), 7.18–7.33 (m, 5H,
C6H5); 13C NMR (CDCl3), d = 14.14, 17.97, 38.89, 41.88, 47.22,
61.22, 61.35, 127.25 (C-2, C-6 aromatic), 127.54, 128.33 (C-3, C-5
aromatic), 141.07, 168.75, 174.23; HRMS: calculated for
[C15H29NO3+H]+: 262.1443; found: 262.1423.
The substitution of 3R,4S-8a with 3R,4R-8b in Section 5.1.9
afforded (4R,5R)-5-methyl-4-phenylpyrrolidin-2-one. Yield: 85%
(375 mg). 1H NMR (CDCl3); d = 1.20 (d, 3H, J = 6.5 Hz, 5-CH3),
2.48–2.57 (m, 1H, 3-CH2), 2.65–2.74 (m, 1H, 3-CH2), 2.98–3.07
(m, 1H, 4-H) 3.65–3.75 (m, 1H, 5-H), 6.76 (br s, 1H, NH), 7.07–
7.33 (m, 5H, C6H5); 13C NMR (CDCl3); d = 20.39, 39.33, 49.66,
57.68, 127.23 (C-2, C-6 aromatic), 127.37, 128.82 (C-3, C-5 aro-
matic), 140.84, 176.48;. HRMS: calculated for [C11H13NO+Na]+:
198.0895; found: 198.0888.
5.1.15. Ethyl erythro-(4S,5R)-2-(5-methyl-4-phenylpyrrolidin-1-
yl)-acetate (4S,5R-10c)
5.1.11. erythro-(4S,5R)-5-Methyl-4-phenylpyrrolidin-2-one
(4S,5R-9c)
The substitution of 4R,5S-9a with 4S,5R-9c in Section 5.1.13
afforded
(4S,5R)-2-(5-methyl-4-phenylpyrrolidin-1-yl)-acetate.
The substitution of 3R,4S-8a with 3S,4R-8c in Section 5.1.9
afforded (4S,5R)-5-methyl-4-phenylpyrrolidin-2-one. Yield: 84%
(371 mg). 1H NMR (CDCl3); d = 0.75 (d, 3H, J = 6.5 Hz, 5-CH3),
2.55–2.69 (m, 2H, 3-CH2), 3.64–3.72 (m, 1H, 4-H), 3.96–4.04 (m,
1H, 5-H), 6.78 (br s, 1H, NH), 7.07–7.33 (m, 5H, C6H5). 13C NMR
(CDCl3); d = 17.53, 35.21, 44.07, 53.72, 126.50, 127.13, 127.91,
128.51, 128.80, 138.83, 177.74; HRMS: calculated for [C11H13NO+
Na]+: 198.0895; found: 198.0901.
Yield: 70% (367 mg). 1H NMR (CDCl3); d = 0.72 (d, 3H, J = 6.6 Hz,
5-CH3), 1.23 (t, 3H, J = 7.0 Hz, CH2CH3), 2.60–2.91 (d, 2H,
J = 8.5 Hz, 3-CH2), 3.65–3.74 (m, 1H, 4-H), 3.66 (d, 2H, J = 17.7 Hz,
NCH2COO), 4.01–4.10 (m, 1H, 5-H), 4.10–4.20 (m, 2H, CH2CH3),
4.38 (d, 1H, J = 17.7 Hz, NCH2COO), 7.09–7.31 (m, 5H, C6H5); 13C
NMR (CDCl3), d = 14.13, 14.65, 35.21, 42.07, 42.29, 57.62, 61.34,
127.14 (C-2, C-6 aromatic), 128.03, 128.51 (C-3, C-5 aromatic),
138.88, 168.89, 174.68; HRMS: calculated for [C15H29NO3+H]+:
262.1443; found: 262.1448.
5.1.12. threo-(4S,5S)-5-Methyl-4-phenylpyrrolidin-2-one (4S,5S-
9d)
5.1.16. Ethyl threo-(4S,5S)-2-(5-methyl-4-phenylpyrrolidin-1-
yl)-acetate (4S,5S-10d)
The substitution of 3R,4S-8a with 3S,4S-8d in Section 5.1.9
afforded (4S,5S)-5-methyl-4-phenylpyrrolidin-2-one. Yield: 84%
(371 mg). 1H NMR (CDCl3); d = 1.20 (d, 3H, J = 6.5 Hz, 5-CH3),
2.48–2.57 (m, 1H, 3-CH2), 2.65–2.74 (m, 1H, 3-CH2), 2.98–3.07
(m, 1H, 4-H) 3.65–3.75 (m, 1H, 5-H), 6.76 (br s, 1H, NH), 7.07–
The substitution of 4R,5S-9a with 4S,5S-9d in Section 5.1.13
afforded
(4S,5S)-2-(5-methyl-4-phenylpyrrolidin-1-yl)-acetate.
Yield: 72% (377 mg). 1H NMR (CDCl3); d = 1.16 (d, 3H, J = 6.3 Hz,
5-CH3), 1.23 (t, 3H, J = 7.0 Hz, CH2CH3), 2.53–2.63 (m, 1H, CH2),