10.1002/adsc.201701304
Advanced Synthesis & Catalysis
calcd for (C12H14NaO3)+ (M+Na)+ 229.0835; found
229.0831.
5-(4-Methoxyphenyl)pyrrolidin-2-one (3e). Yellowish
solid (26 mg, 60% yield). Rf (5% MeOH/CH2Cl2): 0.43. Mp:
115-116 °C. IR (KBr): ν 3426, 3055, 2986, 1696, 1265,
1035, 739 cm-1. 1H NMR (300.13 MHz, CDCl3): δ 1.96 (m,
1H), 2.39-2.56 (m, 3H), 3.80 (s, 3H), 4.71 (t, 3JHH = 7.0 Hz,
Methyl 4-(4-fluorophenyl)-4-oxobutanoate (1g).
White solid (210 mg, 98% yield). Rf (50% EtOAc/Hexane):
0.37. Mp: 51-52 °C. IR (KBr): ν 3064, 2954, 2918, 2850,
1
3
1738, 1599, 1439, 1412, 1268, 1157, 737 cm-1. H NMR
1H), 6.44 (br s, 1H), 6.89 (d, JHH = 8.7 Hz, 2H), 7.21 (d,
(300.13 MHz, CDCl3): δ 2.76 (t, 3JHH = 6.6 Hz, 2H), 3.29 (t,
3JHH = 6.6 Hz, 2H), 3.70 (s, 3H), 7.13 (t, 3JHH = 8.6 Hz, 2H),
3JHH = 8.7 Hz, 2H). 13C NMR (300.13 MHz, CDCl3): δ 30.4
(CH2), 31.5 (CH2), 55.3 (CH3), 57.6 (CH), 114.2 (2 CH),
126.8 (2 CH), 134.4 (C), 159.2 (C), 178.4 (C). HRMS (ESI+,
3
3
8.01 (dd, JHH = 8.9 Hz, JHF = 5.4 Hz, 2H). 13C NMR
(300.13 MHz, CDCl3): δ 27.9 (CH2), 33.2 (CH2), 51.8 (CH3), m/z): calcd for (C11H13NNaO2)+ (M+Na)+ 214.0838; found
115.6 (d, 2JCF = 21.9 Hz, 2 CH), 130.6 (d, JCF = 9.3 Hz, 2
214.0836.
3
4
1
CH), 132.9 (d, JCF = 2.8 Hz, C), 165 (d, JCF = 254.8 Hz,
C), 173.2 (C), 196.4 (C). HRMS (ESI+, m/z): calcd for
(C11H11FNaO3)+ (M+Na)+ 233.0584; found 233.0583.
5-(4-Methylphenyl)pyrrolidin-2-one (3f). White solid
(31 mg, 73% yield). Rf (5% MeOH/CH2Cl2): 0.5. Mp: 89-
90 °C. IR (KBr): ν 3425, 3054, 2985, 2922, 2852, 1695,
1266, 1156, 738, 705 cm-1. 1H NMR (300.13 MHz, CDCl3):
δ 1.93-2.06 (m, 1H), 2.38 (s, 3H), 2.45 (m, 2H), 2.51-2.62
Methyl
4-(4-ethylphenyl)-4-oxobutanoate
(1h).
Yellowish oil (528 mg, 98% yield). Rf (50%
EtOAc/Hexane): 0.5. IR (NaCl): ν 3057, 2969, 2920, 2877,
3
(m, 1H), 4.73 (t, JHH = 7.1 Hz, 1H), 6.23 (br s, 1H), 7.14-
2850, 1737, 1607, 1439, 1415, 1266, 1169, 738 cm-1. H
7.28 (m, 4H). 13C NMR (300.13 MHz, CDCl3): δ 21.0 (CH3),
30.3 (CH2), 31.4 (CH2), 57.8 (CH), 126.2 (2 CH), 129.2 (2
CH), 137.7 (C), 139.4 (C), 178.4 (C). HRMS (ESI+, m/z):
calcd for (C11H13NNaO)+ (M+Na)+ 198.0889; found
198.0888.
1
NMR (300.13 MHz, CDCl3): δ 1.26 (t, 3JHH = 7.6 Hz, 3H),
2.67-2.78 (m, 4H), 3.30 (t, 3JHH = 6.7 Hz, 2H), 3.70 (s, 3H),
7.28 (d, 3JHH = 8.3 Hz, 2H), 7.91 (d, 3JHH = 8.3 Hz, 2H). 13
C
NMR (300.13 MHz, CDCl3): δ 15.1 (CH3), 28.0 (CH2), 28.9
(CH2), 33.2 (CH2), 51.7 (CH3), 128.0 (2 CH), 128.2 (2 CH),
134.2 (C), 150.1 (C), 173.4 (C), 197.6 (C). HRMS (ESI+,
m/z): calcd for (C13H16NaO3)+ (M+Na)+ 243.0992; found
243.0990.
5-(4-Fluorophenyl)pyrrolidin-2-one (3g). White solid
(25 mg, 59% yield). Rf (5% MeOH/CH2Cl2): 0.5. Mp: 138-
139 °C. IR (KBr): ν 3425, 3055, 2986, 2924, 1698, 1606,
1512, 1422, 1265, 738 cm-1. 1H NMR (300.13 MHz,
CDCl3): δ 1.88-2.00 (m, 1H), 2.41-2.52 (m, 2H), 2.58 (m,
1H), 4.78 (t, 3JHH = 7.1 Hz, 1H), 7.05 (t, 3JHH = 8.6 Hz, 2H),
Methyl 5-oxo-phenylpentanoate (1i). Yellowish oil
(489 mg, 92% yield). Rf (50% EtOAc/Hexane): 0.57. IR
(KBr): ν 3057, 2986, 2953, 2848, 1735, 1449, 1419, 1372,
1266, 1179, 704, 692 cm-1. 1H NMR (300.13 MHz, CDCl3):
δ 2.08 (quin, 3JHH = 7.1 Hz, 2H), 2.44 (t, 3JHH = 7.2 Hz, 2H),
3.04 (t, 3JHH = 7.1 Hz, 2H), 3.66 (s, 3H), 7.44 (m, 2H), 7.54
7.08 (s, 1H), 7.29 (dd, 3JHH = 8.7 Hz, 4JHF = 5.2 Hz, 2H). 13
C
NMR (300.13 MHz, CDCl3): δ 30.3 (CH2), 31.4 (CH2), 57.4
2
3
(CH), 115.7 (d, JCF = 21.6 Hz, 2 CH), 127.3 (d, JCF = 8.1
Hz, 2 CH), 130.7 (d, 4JCF = 3.1 Hz, C), 162.0 (d, 1JCF = 246.1
Hz, C), 178.3 (C). HRMS (ESI+, m/z): calcd for
(C10H10FNNaO)+ (M+Na)+ 202.0639; found 202.0635.
5-(4-Ethylphenyl)pyrrolidin-2-one (3h). Yellowish
solid (30 mg, 69% yield). Rf (5% MeOH/CH2Cl2): 0.55. Mp:
82-83 °C. IR (KBr): ν 3425, 3054, 2984, 2970, 2931, 1696,
3
4
(m, 1H), 7.95 (dd, JHH = 8.4 Hz, JHH = 1.4 Hz, 2H). 13C
NMR (300.13 MHz, CDCl3): δ 19.3 (CH2), 33.0 (CH2), 37.4
(CH2), 51.5 (CH3), 127.9 (2 CH), 128.5 (2 CH), 133.0 (CH),
136.7 (C), 173.6 (C), 199.3 (C). HRMS (ESI+, m/z): calcd
for (C12H14NaO3)+ (M+Na)+ 229.0835; found 229.0835.
Methyl 5-(4-fluorophenyl)-5-oxopentanoate (1j).
White solid (504 mg, 91% yield). Rf (50% EtOAc/Hexane):
0.33. Mp: 46-47 °C. IR (KBr): ν 3059, 2953, 2849, 1735,
1
1422, 1265, 739 cm-1. H NMR (300.13 MHz, CDCl3): δ
1.24 (t, 3JHH = 7.6 Hz, 3H), 1.99 (m, 1H), 2.37-2.47 (m, 2H),
2.48-2.60 (m, 1H), 2.66 (q, 3JHH = 7.6 Hz, 2H), 4.74 (t, 3JHH
= 7.1 Hz, 1H), 6.05 (br s, 1H), 7.24 (m, 4H). 13C NMR
(300.13 MHz, CDCl3): δ 15.5 (CH3), 28.4 (CH2), 30.3 (CH2),
31.4 (CH2), 57.9 (CH), 125.6 (2 CH), 128.3 (2 CH), 139.6
(C), 144.1 (C), 178.3 (C). HRMS (ESI+, m/z): calcd for
(C12H15NNaO)+ (M+Na)+ 212.1046; found 212.1044.
1
1598, 1410, 1371, 1267, 1157, 738 cm-1. H NMR (300.13
MHz, CDCl3): δ 2.06 (quin, 3JHH = 7.1 Hz, 2H), 2.46 (t, 3JHH
= 7.1 Hz, 2H), 3.04 (t, 3JHH = 7.1 Hz, 2H), 3.60 (s, 3H), 7.14
(t, 3JHH = 8.6 Hz, 2H), 8.00 (dd, 3JHH = 8.9 Hz, 3JHF = 5.4 Hz,
2H). 13C NMR (300.13 MHz, CDCl3): δ 19.3 (CH2), 33.0
2
(CH2), 37.3 (CH2), 51.6 (CH3), 115.6 (d, JCF = 21.8 Hz, 2
6-Phenylpiperidin-2-one (3i). White solid (12 mg, 48%
yield). Rf (5% MeOH/CH2Cl2): 0.46. Mp: 112-113 °C. IR
(KBr): ν 3389, 3054, 2985, 2957, 293, 2853, 1657, 1265,
738, 704 cm-1. 1H NMR (300.13 MHz, CDCl3): δ 1.63-1.74
(m, 1H), 1.76-1.86 (m, 1H), 1.87-1.99 (m, 1H), 2.03-2.17
CH), 130.6 (d, 3JCF = 9.4 Hz, 2 CH), 133.2 (d, 4JCF = 3.3 Hz,
1
C), 165.0 (d, JCF = 254.9 Hz, C), 173.6 (C), 197.7 (C).
HRMS (ESI+, m/z): calcd for (C12H13FNaO3)+ (M+Na)+
247.0741; found 247.0742.
3
(m, 1H), 2.37-2.52 (m, 2H), 4.57 (dd, JHH = 8.8, 4.6 Hz,
1H), 6.02 (s, 1H), 7.28-7.43 (m, 5H). 13C NMR (300.13
MHz, CDCl3): δ 19.7 (CH2), 31.3 (CH2), 32.2 (CH2), 57.8
(CH), 126.0 (2 CH), 127.9 (CH), 128.8 (2 CH), 142.4 (C),
172.3 (C). HRMS (ESI+, m/z): calcd for (C11H13NNaO)+
(M+Na)+ 198.0889; found 198.0887.
General procedure for the chemical synthesis of racemic
γ-lactams 3d-h and δ-lactams 3i and 3j. In order to
develop robust analytical methods for monitoring the
biotransaminations, the synthesis of racemic lactams was
previously chemically performed in the following manner:
Ammonium acetate (200 mg, 2.6 mmol) and sodium
cyanoborohydride (33 mg, 0.52 mmol) were successively
added to a solution of the corresponding keto ester 1d-j
(0.26 mmol) in dry MeOH (1.0 mL) under inert atmosphere.
The mixture was stirred at room temperature during 16 h
and, after this time, H2O (5 mL) was added to quench the
reaction. The solution was basified until pH around 11 by
adding a saturated aqueous solution of Na2CO3. Then the
mixture was extracted with Et2O (3 x 10 mL) and the
organic layers were combined, dried over Na2SO4 and
concentrated under reduced pressure. The product was
purified by chromatography column on silica gel (2%
MeOH/CH2Cl2), affording the racemic lactams 3d-j (48-
74%).
6-(4-Fluorophenyl)piperidin-2-one (3j). White solid
(11 mg, 50% yield). Rf (5% MeOH/CH2Cl2): 0.54. Mp: 99-
100 °C. IR (KBr): ν 3389, 3055, 2986, 2930, 1659, 1265,
1
739 cm-1. H NMR (300.13 MHz, CDCl3): δ 1.59-1.70 (m,
1H), 1.71-1.86 (m, 1H), 1.87-1.98 (m, 1H), 2.11 (m, 1H),
3
2.37-2.56 (m, 2H), 4.56 (dd, JHH = 8.9, 4.5 Hz, 1H), 6.02
3
(br s, 1H), 7.08 (t, JHH = 8.6 Hz, 2H), 7.29 (m, 2H). 13C
NMR (300.13 MHz, CDCl3): δ 19.8 (CH2), 31.2 (CH2), 32.3
(CH2), 57.2 (CH), 115.7 (d, 2JCF = 21.6 Hz, 2 CH), 127.7 (d,
3JCF = 8.2 Hz, 2 CH), 138.2 (d, 4JCF = 2.9 Hz, C), 164.0 (d,
1JCF = 246.8 Hz, C), 172.2 (C). HRMS (ESI+, m/z): calcd for
(C11H12FNNaO)+ (M+Na)+ 216.0795; found 216.0793.
General protocol for the transformation of γ- and δ-keto
esters 1a-j into optically active lactams using
commercially available transaminases. In a 1.5 mL
5-Phenylpyrrolidin-2-one (3d). White solid (29 mg,
74% yield). Rf (5% MeOH/CH2Cl2): 0.38. Mp: 107-108 °C.
IR (KBr): ν 3055, 2959, 2926, 2872, 2858, 1687, 1266, 1157, Eppendorf tube, transaminase (2 mg) and the corresponding
740, 705 cm-1. 1H NMR (300.13 MHz, CDCl3): δ 1.94-2.06
(m, 1H), 2.38-2.52 (m, 2H), 2.54-2.66 (m, 1H), 4.78 (t, 3JHH
= 7.1 Hz, 1H), 6.01 (br s, 1H), 7.28-7.42 (m, 5H). 13C NMR
(300.13 MHz, CDCl3): δ 30.2 (CH2), 31.4 (CH2), 58.0 (CH),
125.6 (2 CH), 127.9 (CH), 128.9 (2 CH), 142.3 (C), 178.4
(C). HRMS (ESI+, m/z): calcd for (C10H11NNaO)+ (M+Na)+
184.0733; found 184.0735.
keto ester (1a-j, 15 or 25 mM) were added in a phosphate
buffer 100 mM pH 7.5 (500 µL, 1 mM PLP, 1 M
isopropylamine), using DMSO (12.5 µL) as cosolvent. The
reaction was shaken at 30 or 45 °C and 250 rpm for 24 h and
stopped by the addition of an aqueous Na2CO3 saturated
solution (200 µL). Then the mixture was extracted with
EtOAc (2 x 500 µL), the organic layers separated by
7
This article is protected by copyright. All rights reserved.