Z. Galla et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
1H, CHN); 4.45–4.52 (d, 1H, J = 10.96 Hz, CH2OH); 4.80–4.88 (d, 1H,
J = 10.96 Hz, CH2OH); 6.52–6.96 (m, 2H, CHCH). Analysis: calculated for
C7H9NO2: C, 60.42; H, 6.52; N, 10.07; found: C, 61.10; H, 6.48; N, 10.02. The
1H NMR (400 MHz, D2O) data for (1S,4R)-6: d = 2.05–2.64 (m, 2H, CH2); 3.56–
3.63 (m, 1H, CHCOOH); 4.39–4.45 (m, 1H, CHNH2); 5.99–6.39 (m, 2H, CHCH).
Analysis: calculated for C6H9NO2: C, 56.68; H, 7.13; N, 11.02; found: C, 56.74;
H, 7.14; N, 10.97.
Acknowledgement
The authors acknowledge the receipt of OTKA Grants K-108943
and K115731 for financial support.
18. Via the procedure described above,13 the reaction of racemic ( )-2 (100 mg,
References
0.71 mmol), benzylamine (79
lL, 0.71 mmol.) and H2O (6.4 lL, 0.35 mmol) in i-
Pr2O (10 mL) in the presence of CAL-B (300 mg, 30 mg mLÀ1) at 60 °C after 55 h
afforded the unreacted (1R,4S)-2 [44 mg, 44%; viscous oil, [
CHCl3), ee = 96%] and amino acid (1R,3S)-8 [39 mg, 43%; [
a]
25 = +49.8 (c 0.72,
a
]
D
2D5 = À11.0 (c 0.30,
H2O), ee = 99%; lit.13 = À10.6 (c 0.35, H2O), ee = 98%; mp >260 °C with decom-
position (recrystallized from H2O/Me2CO), lit.13 mp >260 °C with decomposi-
tion (recrystallized from H2O/Me2CO)]. The 1H NMR (400 MHz, CDCl3, 25 °C,
TMS) data for (1R,4S)-2: d = 1.35–1.96 (m, 6H, 3ÂCH2); 2.75–2.86 (m, 1H,
CHCO); 3.95–4.06 (m, 1H, CHN); 4.49–4.87 (m, 2H, CH2OH). Analysis:
calculated for C7H11NO2: C, 59.56; H, 7.85; N, 9.92; found: C, 59.62; H, 7.89;
N, 9.86. The 1H NMR (400 MHz, D2O) data for (1R,3S)-8: d = 1.72–2.41 (m, 6H,
3ÂCH2); 2.84–2.96 (m, 1H, CHCOOH); 3.79–3.89 (m, 1H, CHNH2). Analysis:
calculated for C6H11NO2: C, 55.80; H, 8.58; N, 10.84; found: C, 55.78; H, 8.60; N,
10.84.
}
8. Evans C. T.; Roberts S. M.; Stanley M. Eur. Pat. Appl. EP 424064 A17 1991, pp 7.
20. The unreacted hydroxymethyl-c-lactam enantiomers [(1S,4R)-1 and (1R,4S)-2]
were dissolved in 18% HCl (10 mL) and kept at reflux for 5 h. The solvents were
evaporated and the products, obtained almost quantitatively, were
recrystallized from EtOH and Et2O. Amino acid hydrochlorides (1R,4S)-6ÁHCl
and (1S,3R)-8ÁHCl obtained as white crystals were characterized as follows:
15. In a typical small-scale experiment, to the racemic substrate (0.05 M solution)
in i-Pr2O (1 mL) CAL-B (30 mg), H2O (0.5 equiv) and then benzylamine
(1 equiv) were added. The mixture was shaken (167 rpm) at 60 °C. The
progress of the reaction was followed by taking samples from the reaction
mixtures and analyzing them by a GC method on a Chrompack Chirasil-Dex CB
column [140 °C for 25 min ? 190 °C (temperature rise 20 °C minÀ1; 140 kPa;
retention times (min), (1S,4R)-1: 5.84 (antipode: 5.66)], (1R,4S)-2: 7.47
(1R,4S)-6ÁHCl: [
a]
25 = +110 (c 0.20 in H2O), ee = 99%; lit.13 = +111.1 (c 0.35,
D
H2O), ee > 99%; mp 205–207 °C, lit.13 208–209 °C. (1S,3R)-8ÁHCl: [
a]
25 = +10 (c
D
0.20, H2O), ee = 96%; lit.13 = +10.7 (c 0.5, H2O), ee = 97%; mp 170–173 °C, lit.13
175–177 °C. The 1H NMR (400 MHz, D2O) data for (1R,4S)-6ÁHCl: d = 2.14–2.83
(m, 2H, CH2); 3.79–3.88 (m, 1H, CHCOOH); 4.45–4.54 (m, 1H, CHNH2); 6.03-
6.36 (m, 2H, CHCH). Analysis: calculated for C6H9NO.2HCl: C, 44.05; H, 6.16; N,
8.56; found: C, 44.15; H, 6.10; N, 8.55. The 1H NMR (400 MHz, D2O) data for
(1S,3R)-8ÁHCl: d = 1.78–2.55 (m, 6H, 3ÂCH2); 3.03–3.14 (m, 1H, CHCOOH);
3.79–3.89 (m, 1H, CHNH2). Analysis: calculated for C6H11NO2ÁHCl: C, 43.51; H,
7.30; N, 8.46; found: C, 43.61; H, 7.35; N, 8.41.
(antipode: 7.11)]. The ee values for the product
c-amino acids [after pre-
column derivatization16 with CH2N2 (Caution! derivatization with CH2N2 should
be performed under a well-ventillating hood)] were determined by a GC method
[120 °C for 25 min ? 160 °C (temperature rise 10 °C minÀ1; 140 kPa; retention
times (min), (1S,4R)-6: 27.38 (antipode: 27.84)], (1R,3S)-8: 28.74 (antipode:
28.98)].
22. The unreacted N-hydroxymethyl-c-lactams (1S,4R)-1 and (1R,4S)-2, (20 mg,
0.14 mmol) were dissolved in MeOH (2 ml). Next, NH4OH (2 ml) was added
and the mixture was stirred at room temperature for 4 h. The solvent was
evaporated, the residue was chromatographed on silica, and elution with ethyl
17. ( )-1 (100 mg, 0.72 mmol) was dissolved in i-Pr2O (10 mL). Next, CAL-B
(300 mg, 30 mg mLÀ1), benzylamine (79
lL, 0.72 mmol) and H2O (6.5 lL,
acetate afforded white crystals of (1S,4R)-3 [15 mg, 95%; [
CHCl3), ee = 99%; lit.13 = +549 (c 0.26, CHCl3) ee > 99%; mp 95–98 °C (recrys-
tallized from i-Pr2O), lit.13 97–100 °C] or (1R,4S)-9 [15 mg, 93%; [ 25 = +125.5
a]
25 = +545 (c 0.3,
D
0.36 mmol) were added and the mixture was shaken in an incubator shaker at
60 °C for 120 min. The reaction was stopped by filtering off the enzyme at 50%
conversion. The solvent was evaporated and the residue was subjected to
a
]
D
(c 0.55, CHCl3), ee = 96%; lit.13 = +158 (c 0.45, CHCl3) ee >99%; mp 78–81 °C
(recrystallized from i-Pr2O), lit.13 78–81 °C]. The 1H NMR (400 MHz, CDCl3,
25 °C, TMS) data for (1S,4R)-3: d = 2.18–2.43 (m, 2H, CH2); 3.18–3.24 (m, 1H,
CHCO); 4.30–4.37 (m, 1H, CHNH); 6.05 (br s, 1H, NH); 6.63–6.82 (m, 2H, CHCH).
Analysis: calculated for C6H7NO: C, 66.04; H, 6.47; N, 12.84; found: C, 66.12; H,
6.38; N, 12.82. The 1H NMR (400 MHz, CDCl3, 25 °C, TMS) data for (1R,4S)-4:
d = 1.33–1.97 (m, 6H, 3ÂCH2); 2.76–2.85 (m, 1H, CHCO); 3.04 (br s, 1H, NH);
3.95–4.08 (m, 1H, CHNH). Analysis: calculated for C6H9NO: C, 64.84; H, 8.16; N,
12.60; found: C, 64.81; H, 8.13; N, 12.68.
column chromatography (EtOAc:n-hexane 1:1). The resulting
c-lactam
(1S,4R)-1 was [49 mg, 49%; viscous oil {[a]
25 = +342 (c 0.50, CHCl3); ee = 99%,
D
lit.19 = +344 (c 2.1, CHCl3); ee > 99%}. The filtered enzyme was washed with
distilled H2O (3 Â 15 mL) and after evaporation of H2O yielded the crystalline
c
-amino acid (1S,4R)-6 [46 mg, 49%;
[
a
]
25 = À240 (c 0.30, H2O), ee = 99%,
D
lit.13 = À243 (c 0.34, H2O), ee > 99%; mp >260 °C with decomposition (recrys-
tallized from H2O/Me2CO), lit.13 mp >260 °C with decomposition (recrystal-
lized from H2O/Me2CO)]. The 1H NMR (400 MHz, CDCl3, 25 °C, TMS) data for
(1S,4R)-1: d = 2.10–2.34 (m, 2H, CH2); 3.31–3.37 (m, 1H, CHCO); 4.30–4.37 (m,