H
K. Kriis et al.
Paper
Synthesis
Hz, 1 H, NCH2Ph), 2.64–2.54 (m, 1 H, H-4), 2.37 (dd, J = 16.1, 3.6 Hz, 1
H, CH2CO), 2.24 (dd, J = 16.2, 9.0 Hz, 1H, CH2CO), 2.24–2.17 (m, 1 H, H-
6), 1.99–1.92 (m, 1 H, H-5), 1.53 (qd, J = 12.5, 4.0 Hz, 1 H, H-5), 1.24 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 170.6, 149.4 (br), 138.0, 136.4, 129.6
(br), 128.5, 128.4, 127.2, 121.3 (br), 120.4 (q, J = 257.7 Hz), 95.2, 70.1,
60.8, 58.7, 51.4, 37.7, 36.8, 28.9, 14.2.
13C NMR (101 MHz, CDCl3): δ = 171.0, 137.7, 135.6, 134.5, 130.1,
129.1, 128.5, 128.4, 127.3, 91.7, 64.0, 60.9, 58.6, 45.9, 33.1, 32.0, 28.1,
14.2.
HRMS (ESI): m/z [M + H]+ for 5d and 6d (diastereomeric mixture):
calcd for (C22H25ClN2O4H)+: 417.1576; found: 417.1574.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-2-(3-methylphenyl)-3-nitropiperi-
din-4-yl]acetate (5e) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-2-(3-
methylphenyl)-3-nitropiperidin-4-yl]acetate (6e)
6c
1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 8.5 Hz, 2 H, 4-CF3OC6H4,
2′,6′-H), 7.33–7.20 (m, 3 H, C6H5), 7.22–7.15 (m, 4 H, C6H5 + 4-
CF3OC6H4, 3′,5′-H), 4.90 (dd, J = 10.3, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1
Hz, 2 H, OCH2CH3), 3.90 (d, J = 10.3 Hz, 1 H, H-2), 3.62 (d, J = 13.3 Hz, 1
H, NCH2Ph), 3.17–3.08 (m, 1 H, H-4), 2.96 (d, J = 13.5 Hz, 1 H, NCH2Ph),
2.79 (ddd, J = 12.4, 4.2, 3.1 Hz, 1 H, H-6), 2.65–2.62 (m, 2 H, CH2CO),
2.29 (td, J = 12.7, 2.7 Hz, 1 H, H-6), 2.03–1.97 (m, 1 H, H-5), 1.78 (dq,
J = 14.2, 2.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3).
The title compounds 5e and 6e were obtained according to the gener-
al procedure as a diastereomeric mixture (39 mg, 73%, 1.3:1 dr); pale
yellow oil.
5e
1H NMR (400 MHz, CDCl3): δ = 7.31–7.15 (m, 5 H, Ar), 7.12–7.05 (m, 4
H, Ar), 4.55 (dd, J = 11.3, 9.6 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.70 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.63 (d, J = 9.6 Hz, 1 H, H-
2), 2.97 (dt, J = 11.9, 3.4 Hz, 1 H, H-6), 2.89 (d, J = 13.5 Hz, 1 H,
NCH2Ph), 2.65–2.54 (m, 1 H, H-4), 2.36 (dd, J = 16.0, 3.6 Hz, 1 H,
CH2CO), 2.33 (s, 3 H, ArCH3), 2.23 (dd, J = 16.0, 9.2 Hz, 1 H, CH2CO),
2.17 (ddd, J = 12.2, 2.6 Hz, 1 H, H-6), 1.98–1.90 (m, 1 H, H-5), 1.50 (qd,
J = 12.6, 3.9 Hz, 1 H, H-5), 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 171.0, 149.2 (br), 138.0, 136.9, 130.2
(br), 128.5, 128.4, 127.2, 121.1 (br), 120.4 (q, J = 257.7 Hz), 91.9, 64.0,
60.9, 58.7, 45.9, 33.1, 32.0, 28.2, 14.2.
HRMS (ESI): m/z [M + H]+ for 5c and 6c (diastereomeric mixture)
calcd for (C23H25F3N2O5H)+: 467.1788; found: 467.1789.
13C NMR (101 MHz, CDCl3): δ = 170.7, 138.6, 138.5, 137.7, 129.6,
128.9, 128.8, 128.5, 128.2, 127.0, 125.2, 95.3, 70.9, 60.7, 58.6, 51.4,
37.77, 37.0, 29.0, 21.5, 14.2.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-2-(4-chlorophenyl)-3-nitropiperi-
din-4-yl]acetate (5d) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-2-(4-
chlorophenyl)-3-nitropiperidin-4-yl]acetate (6d)
6e
The title compounds 5d and 6d were obtained according to the gener-
al procedure as a diastereomeric mixture (44 mg, 79%, 1.3:1 dr); pale
yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.15 (m, 5 H, Ar), 7.12–7.05 (m, 4
H, Ar), 4.97 (dd, J = 10.3, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.81 (d, J = 10.3 Hz, 1 H, H-2), 3.66 (d, J = 13.4 Hz, 1 H,
NCH2Ph), 3.17–3.06 (m, 1 H, H-4), 2.92 (d, J = 13.3 Hz, 1 H, NCH2Ph),
2.76 (dt, J = 12.3, 3.7 Hz, 1 H, H-6), 2.65 (d, J = 7.3 Hz, 2 H, CH2CO), 2.33
(s, 3 H, ArCH3), 2.28 (ddd, J = 12.7, 2.8 Hz, 1 H, H-6), 2.02–1.96 (m, 1 H,
H-5), 1.75 (dq, J = 14.1, 2.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (95:2:4), flow rate 1.0
mL/min, detection at λ = 230 nm: for 5d major enantiomer tR = 18.5
min, minor enantiomer tR = 12.0 min; 89% ee; and for 6d major enan-
tiomer tR = 14.0 min, minor enantiomer tR = 10.4 min; 94% ee.
5d
13C NMR (101 MHz, CDCl3): δ = 171.2, 138.6, 138.3, 138.0, 129.5,
129.4, 128.6, 128.5, 128.2, 127.0, 125.8, 91.9, 64.8, 60.8, 58.6, 45.9,
33.1, 32.1, 28.3, 21.4, 14.2.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.30 (m, 3 H, C6H5 + 4-ClC6H4,
3′,5′-H), 7.30–7.21 (m, 4 H, C6H5), 7.21–7.14 (m, 2 H, 4-ClC6H4, 2′,6′-
H), 4.56 (dd, J = 11.1, 9.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.70 (d, J = 9.8 Hz, 1 H, H-2), 3.69 (d, J = 13.3 Hz, 1 H,
NCH2Ph), 3.03 (dt, J = 12.0, 3.3 Hz, 1 H, H-6), 2.96 (d, J = 13.5 Hz, 1 H,
NCH2Ph), 2.63–2.54 (m, 1 H, H-4), 2.37 (dd, J = 16.1, 3.6 Hz, 1 H,
CH2CO), 2.24 (dd, J = 16.2, 8.9 Hz, 1 H, CH2CO), 2.23 (td, J = 12.3, 2.6
Hz, 1 H, H-6), 2.00–1.93 (m, 1 H, H-5), 1.55 (qd, J = 12.5, 4.1 Hz, 1 H,
H-5), 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3).
HRMS (ESI): m/z [M + H]+ for 5e and 6e (diastereomeric mixture) cal-
cd for (C23H28N2O4H)+: 397.2122; found: 397.2130.
Ethyl 2-[(2R*,3S*,4S*)-1-Benzyl-3-nitro-2-(4-nitrophenyl)piperi-
din-4-yl]acetate (5f) and Ethyl 2-[(2R*,3S*,4R*)-1-Benzyl-3-nitro-
2-(4-nitrophenyl)piperidin-4-yl]acetate (6f)
13C NMR (101 MHz, CDCl3): δ = 170.6, 137.4, 135.9, 134.8, 129.6,
129.4, 128.6, 128.4, 127.4, 94.9, 77.3, 70.1, 60.8, 58.5, 51.4, 37.6, 36.8,
28.7, 14.2.
The title compounds 5f and 6f were obtained according to the general
procedure as a diastereomeric mixture (50 mg, 85%, 1.1:1 dr); pale
yellow oil.
HPLC: Chiralcel AD-H, n-hexane/i-PrOH/EtOH (88:7:5), flow rate 1.0
mL/min, detection at λ = 230 nm: for 5f major enantiomer tR = 26.0
min, minor enantiomer tR = 24.2 min; 88% ee; and for 6f major enan-
tiomer tR = 28.7 min, minor enantiomer tR = 20.4 min; 93% ee.
6d
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 8.1 Hz, 2H, 4-ClC6H4, 3′,5′-
H), 7.39–7.30 (m, 1 H, Ar), 7.30–7.21 (m, 4 H, Ar), 7.21–7.14 (m, 2 H,
Ar), 4.93 (dd, J = 10.4, 4.9 Hz, 1 H, H-3), 4.12 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 3.87 (d, J = 10.4 Hz, 1 H, H-2), 3.65 (d, J = 13.4 Hz, 1 H,
NCH2Ph), 3.19–3.08 (m, 1 H, H-4), 2.97 (d, J = 13.4 Hz, 1 H, NCH2Ph),
2.80 (dt, J = 12.4, 3.6 Hz, 1 H, H-6), 2.64–2.61 (m, 2 H, CH2CO), 2.31
(ddd, J = 12.7, 2.7 Hz, 1 H, H-6), 2.05–1.97 (m, 1 H, H-5), 1.77 (dq, J =
14.3, 2.8 Hz, 1 H, H-5), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3).
5f
1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 9.0 Hz, 2 H, 4-NO2C6H4,
3′,5′-H), 7.64 (d, J = 8.1 Hz, 2 H, 4-NO2C6H4, 2′,6′-H), 7.31–7.22 (m, 3 H,
C6H5), 7.20–7.12 (m, 2 H, C6H5), 4.56 (dd, J = 11.3, 9.6 Hz, 1 H, H-3),
4.13 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.83 (d, J = 9.6 Hz, 1 H, H-2), 3.58 (d,
J = 13.6 Hz, 1 H, NCH2Ph), 3.03 (ddd, J = 12.0, 4.0, 2.9 Hz, 1 H, H-6),
3.02 (d, J = 13.4 Hz, 1 H, NCH2Ph), 2.66–2.56 (m, 1 H, H-4), 2.38 (dd, J =
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K