The Journal of Organic Chemistry
Note
column chromatography (EtOAc:petroleum ether, 2:8) to furnish 2,3-
disubstituted piperidine derivative (9a−9i).
2H), 3.08−2.92 (m, 2H), 1.94−1.77 (m, 2H), 1.68−1.56 (m, 1H),
1.52−1.47(m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.3, 155.6,
141.5, 136.5, 136.3, 128.7, 128.6, 128.4, 128.2, 127.9, 127.2, 125.09,
124.9, 67.7, 67.1, 56.2, 48.9, 39.7, 24.0, 19.7.HRMS (ESI) Calcd. for
C25H26N2O4SNa(M + Na)+ 473.1511, found 473.1511.
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-phenylpiperi-
dine-1-carboxylate (9a). Synthesized according to the general
procedure B. Product was isolated as white solid (0.18 g, 81% yield):
Rf = 0.6 petroleum ether:EtOAc (50:50), [α2D5] −2 (c 1, CHCl3); mp =
127−129 °C; IR (cm−1) 3390, 1691.1518; 1H NMR (400 MHz,
CDCl3) δ 7.28 (m, 13H), 7.17 (bm, 2H), 5.44 (d, J = 6.4 Hz, 1H),
5.21−4.90 (m, 4H), 4.35 (d, J = 9.1 Hz, 1H), 4.21−4.04 (m, 2H), 3.22
(m, 1H), 1.93−1.85 (m, 2H), 1.81−1.62 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 155.9, 155.5, 138.4, 136.6, 136.4, 129.2, 128.7, 128.1,
128.3, 128.0, 127.8, 67.4, 66.9, 57.4, 50.2, 40.5, 26.1, 24.1; HRMS
(ESI) Calcd. for C27H29N2O4 (M + H)+ 445.2127, found 445.2128.
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(p-tolyl)-
piperidine-1-carboxylate (9b). Synthesized according to the
general procedure B. Product was isolated as colorless oil (0.176 g,
77% yield): Rf = 0.6 petroleum ether:EtOAc (50:50), [α2D5] −4.1 (c 1,
CHCl3); IR (cm−1) 3329, 1695, 1516; 1H NMR (400 MHz, CDCl3) δ
7.39−7.25 (m, 8H), 7.19 (m, 4H), 7.08 (d, J = 7.9 Hz, 2H), 5.41 (d, J
= 6.3 Hz, 1H), 5.20−4.93 (m, 4H), 4.38 (d, J = 9.1 Hz, 1H), 4.12 (m,
2H), 3.20 (t, J = 12.9 Hz, 1H), 2.32 (s, 3H), 1.89 (d, 2H), 1.69 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 155.8, 155.5, 137.6, 136.7,
136.5, 135.2, 129.4, 129.2, 128.6, 128.5, 128.3, 128.0, 127.9, 77.5, 77.2,
76.8, 67.4, 66.9, 57.2, 50.2, 40.4, 26.2, 24.2, 21.1; HRMS (ESI) Calcd.
for C28H31N2O4 (M + Na)+ 459.2284, found 459.2285.
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(4-
methoxyphenyl)piperidine-1-carboxylate (9g). Synthesized ac-
cording to the general procedure B. Product was isolated as colorless
viscous oil (0.187 g, 79% yield): Rf = 0.6 petroleum ether:EtOAc
1
(50:50), [α2D5] −24.1 (c 1, CHCl3); IR (cm−1) 3329, 1695, 1516; H
NMR (400 MHz, CDCl3) δ 7.47−7.24 (m, 10H), 7.14 (d, J = 8.5 Hz,
2H), 6.88 (d, J = 8.7 Hz, 2H), 5.44 (s, 1H), 5.30 (m, 1H), 5.20−5.05
(m, 4H), 4.52 (d, J = 6.0 Hz, 1H), 4.20−4.09 (m, 1H), 3.80 (s, 3H),
2.89 (t, J = 11.3 Hz, 1H), 1.73 −1.58 (m, 4H); 13C NMR (101 MHz,
CDCl3) δ 158.7, 156.9, 155.8, 136.6, 136.4, 129.0, 128.7, 128.3, 128.4,
128.1, 127.8, 127.6, 114.3, 67.0, 58.2, 55.4, 48.0, 39.9, 23.7, 19.8;
HRMS (ESI) Calcd. for C28H31N2O5 (M + H)+ 475.2233, found
475.2237.
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(3-
methoxyphenyl)piperidine-1-carboxylate (9h). Synthesized ac-
cording to the general procedure B. Product was isolated as colorless
viscous oil (0.184 g, 78% yield): Rf = 0.6 petroleum ether:EtOAc
(50:50), [α2D5] −10 (c 1, CHCl3), IR (cm−1) 3331, 1692, 1514; H
1
NMR (400 MHz, CDCl3) δ 7.40−7.24 (m, 9H), 7.20 (s, 2H), 6.86
(m, 3H), 5.42 (d, J = 5.8 Hz, 1H), 5.18−4.95 (m, 4H), 4.44 (d, J = 8.8
Hz, 1H), 4.18−4.05 (m, 2H), 3.69 (s, 3H), 3.28−3.17 (m, 1H), 1.98−
1.83 (m, 2H), 1.83−1.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
159.7, 155.8, 155.5, 139.8, 136.6, 136.4, 129.6, 128.7, 128.6, 128.5,
128.3, 128.2, 128, 127.9, 121.3, 115.4, 113.1, 67.4, 66.9, 57.4, 55.2,
50.1, 40.5, 26.8, 24.1; HRMS (ESI) Calcd. for C28H30N2O5Na (M +
Na)+ 497.2052, found 497.2051.
(2R,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(furan-2-yl)-
piperidine-1-carboxylate (9c). Synthesized according to the general
procedure B. Product was isolated as colorless viscous oil (0.160 g,
74% yield): Rf = 0.6 petroleum ether:EtOAc (50:50), [α2D5] −19.6 (c 1,
CHCl3); IR (cm−1) 3326, 1694, 1516; 1H NMR (400 MHz, CDCl3) δ
7.41−7.27 (m, 10H), 6.34 (dd, J = 3.1, 1.9 Hz, 1H), 6.16 (bs, 1H),
5.45 (bs, 1H), 5.26 (d, J = 7.7 Hz, 1H), 5.21−5.01 (m, 4H), 4.39 (s,
1H), 4.09 (d, J = 6.6 Hz, 1H), 2.92 (t, J = 12 Hz, 1H), 1.84−1.75 (m,
2H), 1.67−1.59 (m, 2H), 1.56−1.47 (m, 1H).; 13C NMR (100 MHz,
CDCl3) δ 155.6, 151.0, 142.2, 136.3, 128.7, 128.6, 128.4, 110.5, 107.7,
67.5, 67.1, 54.6, 47.0, 40.2, 24.6, 19.7; HRMS (ESI) Calcd. For
C25H26N2O5Na (M + Na)+ 457.1739, found 457.1742.
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(2-
methoxyphenyl)piperidine-1-carboxylate (9i). Synthesized ac-
cording to the general procedure B. Product was isolated in 72% yield
as colorless viscous oil (0.17g, 72% yield): Rf = 0.6 petroleum
ether:EtOAc (50:50), [αD25] + 2.6 (c 1, CHCl3), IR (cm−1) 3428, 1695,
1
1413; H NMR (400 MHz, CDCl3) δ 7.38−7.33 (m, 5H), 7.25−7.21
(m, 4H), 7.16−7.08 (m, 3H), 6.91−6.85 (m, 2H), 5.43 (d, J = 2.5 Hz,
1H), 5.29 (d, J = 8.2 Hz, 1H), 5.11−5.06 (m, 4H), 4.5 (bs, 1H), 4.28−
4.21 (m, 1H), 3.8(s, 3H), 3.35−3.28 (m, 1H), 1.80−1.71 (m, 2H),
1.64−1.58 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 157.0, 156.7,
145.2, 136.6, 131.1, 130.4, 128.6, 128.4, 128.2, 127.9, 127.5, 126.9,
120.4, 110.9, 67.3, 66.8, 56.6, 55.4, 41.5, 41.3, 24.0, 19.2; HRMS(ESI)
Calcd. for C28H30N2O5Na (M + Na)+ 497.2052, found 497.2045.
Synthesis of 1,2-Amino Alcohol (10). BF3·OEt2 (0.192 mL, 1.53
mmol) was added to a solution of Et3SiH (0.6 g, 5.1 mmol) in CH2Cl2
(2 mL) at room temperature. The solution was stirred for 5 min and
then transferred via cannula to a stirred solution of ketone 8a (0.2 g,
0.51 mmol) in CH2Cl2 (5 mL) at −78 °C. The reaction mixture was
stirred at −78 °C for 1 h, whereupon the cooling-bath was removed
and stirring was continued at room temperature for an additional 1 h.
The reaction mixture was recooled to −78 °C and poured into a
mixture of saturated aqueous NaHCO3. The organic layers were
separated, and the aqueous phase was extracted with CH2Cl2, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to afford a white solid 10 (0.184 g, 92% yield): Rf = 0.4
petroleum ether:EtOAc (50:50), [α2D5] −27.8 (c 1, CHCl3); mp =116−
117 °C; IR (cm−1) 3290, 1686, 1545; 1H NMR (400 MHz, DMSO-d6)
δ 7.43−7.07 (m, 16H), 7.04 (d, J = 9.2 Hz, 1H), 5.35 (d, J = 4.9 Hz,
1H), 5.06−4.76 (m, 4H), 4.45 (t, J = 5.5 Hz, 1H), 3.52 (m, 1H), 2.90
(m, 2H), 1.63−1.11 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ
156.1, 155.8, 143.7, 137.4, 137.3, 128.4, 128.3, 127.75, 127.7, 127.6,
127.3, 126.7, 126.5, 74.7, 65.1, 64.8, 56.8, 40.5, 26.5, 26.3 HRMS (ESI)
Calcd. for C27H30N2O5Na (M + Na)+ 485.2052, found 485.2055.
Asymmetric Synthesis of (+)-CP-99,994. A mixture of 9a (0.4 g,
0.87 mmol), and Pd/C (10%, 0.1 g), in MeOH (5 mL) was stirred
under an atmosphere of H2 at rt for 6 h. The crude mixture was filtered
through a pad of Celite, and the filtrate was concentrated under
vacuum to give crude diamine. To a solution of the crude diamine in
CH2Cl2 (5 mL) and 2-methoxybenzaldehyde (0.118 g, 0.87 mmol)
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(4-
fluorophenyl)piperidine-1-carboxylate (9d). Synthesized accord-
ing to the general procedure B. Product was isolated as a white solid
(0.184 g, 80% yield): Rf = 0.6 petroleum ether:EtOAc (50:50), [α2D5]
−2.1 (c 1, CHCl3); mp = 139−141 °C; IR (cm−1) 3322, 1692, 1656,
1529; 1H NMR (400 MHz, CDCl3) δ 7.43−7.23 (m, 13H), 6.95 (t, J
= 8.6 Hz, 2H), 5.46 (d, J = 6.4 Hz, 1H), 5.21−4.94 (m, 4H), 4.32 (d, J
= 8.6 Hz, 1H), 4.13 (d, J = 11.9 Hz, 2H), 3.20 (t, J = 14.7 Hz, 1H),
1.98−1.87 (m, 2H), 1.86−1.61 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 155.8, 155.4, 136.6, 136.4, 130.8, 130.8, 128.7, 128.5, 128.4,
128.1, 127.9, 115.7, 115.4, 67.5, 67.0, 56.8, 50.1, 40.4, 26.0, 24.0;
HRMS (ESI) Calcd. for C27H28FN2O4 (M + H)+ 463.2033, found
463.2037.
(2S,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(4-
chlorophenyl)piperidine-1-carboxylate (9e). Synthesized accord-
ing to the general procedure B. Product was isolated as colorless
viscous oil (0.198 g, 83% yield): Rf = 0.6 petroleum ether:EtOAc
(50:50), [α2D5] −4.6 (c 1, CHCl3); IR (cm−1) 3341, 1694, 1646, 1530;
1H NMR (400 MHz, CDCl3) δ 7.38−7.25 (m, 10H), 7.20 (d, J = 2.7
Hz, 3H), 7.17 (s, 2H), 5.43 (d, J = 6.5 Hz, 1H), 5.16−4.87 (m, 4H),
4.33 (d, J = 8.8 Hz, 1H), 4.15−4.04 (m, 2H), 3.22−3.14 (m, 1H),
1.91−1.83 (m, 2H),1.78−1.68 (m, 1H), 1.67−157 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 155.8, 155.4, 137.0, 136.5, 136.3, 133.8, 130.4,
128.7, 128.8, 128.5, 128.4, 128.4, 128.1, 127.9, 127.8, 67.5, 67.5, 67.0,
56.8, 50.1, 40.6, 25.9, 23.98; HRMS (ESI) Calcd. for C27H28ClN2O4
(M + H)+ 479.1738, found 479.1746.
(2R,3S)-Benzyl 3-(benzyloxycarbonylamino)-2-(thiophen-2-
yl)piperidine-1-carboxylate (9f). Synthesized according to the
general procedure B. Product was isolated as colorless viscous oil (0.17
g, 76% yield): Rf = 0.6 petroleum ether:EtOAc (50:50), [α2D5] −16.7 (c
1, CHCl3); IR (cm−1) 3390, 1694, 1518; 1H NMR (400 MHz, CDCl3)
δ 7.32 (m, 10H), 6.98−6.92 (m, 1H), 5.63 (s, 1H), 5.26 (d, J = 8.4 Hz,
1H), 5.18−5.03 (m, 4H), 4.37 (d, J = 8.0 Hz, 1H), 4.18−3.99 (m,
E
dx.doi.org/10.1021/jo302181k | J. Org. Chem. XXXX, XXX, XXX−XXX