T. Ezawa et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
1.06–1.15, 1.19–1.35, 1.51–1.69, 1.74–1.81 (m, m, m, m, m, m, 1H,
1H, 1H, 2H, 4H, 1H, cyclohexylCH2 ꢁ5), 2.95 (dd, J = 8.2, 13.7 Hz,
1H, CHCHAC6H5), 3.15 (dd, J = 5.7, 13.7 Hz, 1H, CHCHBC6H5),
3.61–3.69 (m, 1H, cyclohexylCH), 4.28 (dd, J = 5.7, 8.2 Hz, 1H,
CHCH2C6H5), 5.10 (s, 2H, OCH2C6H5), 5.25, 5.40 (br, br, 1H, 1H,
NH ꢁ2), 7.19–7.38 (m, 10H, C6H5 ꢁ2); 13C NMR (100 MHz, CDCl3):
d 24.6, 25.4, 32.7, 32.8, 39.2, 48.2, 56.6, 67.0, 127.0, 128.1, 128.2,
128.6, 128.7, 129.4, 136.2, 136.6, 155.8, 169.4; IR (KBr,
vmax/cmꢀ1) = 3317 (CONH), 3275 (CONH), 1689 (CON), 1647
4.4.8. Cbz-L-Phe-NHOH 6ah
29
129 mg (86%); colorless solid; mp: 139–141 °C; [
a
d
]
D = ꢀ11.8
(c 1.00, MeOH); 1H NMR (400 MHz, DMSO-d6):
2.78 (dd,
J = 10.0, 13.7 Hz, 1H, CHCHAC6H5), 2.89 (dd, J = 4.9, 13.7 Hz, 1H,
CHCHBC6H5), 4.10 (ddd, J = 4.9, 8.8, 10.0 Hz, 1H, CHCH2), 4.92 (d,
J = 13.3 Hz, 1H, OCHAC6H5), 4.95 (d, J = 13.3 Hz, 1H, OCHBC6H5),
7.18–7.36 (m, 10H, C6H5 ꢁ2), 7.62 (d, J = 8.8 Hz, 1H, NHCH), 8.89
(s, 1H, NHOH), 10.73 (s, 1H, NHOH); 13C NMR (100 MHz, DMSO-
d6): d 37.6, 53.9, 65.1, 126.2, 127.4, 127.6, 128.0, 128.2, 129.1,
136.9, 137.8, 155.6, 168.0; IR (KBr, vmax/cmꢀ1) = 3315 (OH), 3255
(CONH), 3143 (CONH), 1701 (CON), 1668 (CON); HRMS (ESI-
(CON); HRMS (ESI-TOF): Calcd for
403.1992, found: 403.1972.
C
23H28N2O3Na (M+Na)+:
TOF): Calcd for
337.1129.
C
17H18N2O4Na (M+Na)+: 337.1159, found:
4.4.4. Cbz-
L-Phe-adamantylNH 6ad
191 mg (87%); colorless solid; mp: 55–57 °C; [
a
]
25 = ꢀ1.1 (c
D
1.00, MeOH); 1H NMR (400 MHz, CDCl3): d 1.59–1.64 (m, 6H,
admantylCH2 ꢁ3), 1.75–1.82 (m, 6H, admantylCH2 ꢁ3), 1.97–2.04
(m, 3H, admantylCH ꢁ3), 2.90 (dd, J = 8.7, 13.4 Hz, 1H,
CHCHAC6H5), 3.14 (dd, J = 5.0, 13.4 Hz, 1H, CHCHBC6H5), 4.25 (dd,
J = 5.0, 8.7 Hz, 1H, CHCH2C6H5), 5.00 (br, 1H, NH), 5.10 (s, 2H,
OCH2C6H5), 5.43 (br, 1H, NH), 7.21–7.38 (m, 10H, C6H5 ꢁ2); 13C
NMR (100 MHz, CDCl3): d 29.3, 36.2, 39.3, 41.3, 52.0, 56.9, 66.9,
127.0, 128.0, 128.2, 128.5, 128.7, 129.5, 136.3, 136.8, 155.8,
169.2; IR (KBr, vmax/cmꢀ1): 3307 (CONH), 1705 (CON), 1655
4.5. Typical procedure for the amidation of (2S,3S)-(+)-2,3-
methano-3-phenylpropanoic acid
hydrochloride 5h
7
with hydroxylamine
To a colorless solution of 162 mg (1.0 mmol) of (2S,3S)-(+)-2,3-
methano-3-phenylpropanoic acid 7 prepared from (2S,3S)-(+)-2,3-
methano-3-phenylpropanol20 in 5 mL of THF were added 105
lL
(1.1 mmol, 1.1 equiv) of ClCO2Et and 419 lL (3.0 mmol, 3.0 equiv)
of Et3N at ꢀ15 °C. After stirring for 10 min at ꢀ15 °C, 1.0 mL of a
2.0 M aqueous solution of hydroxylamine hydrochloride (2.0
mmol, 2.0 equiv) was added at ꢀ15 °C to the colorless suspension.
The mixture was stirred for 4 h at ꢀ15 °C after which 5 mL of 1.0 M
aqueous HCl solution were added to the resulted mixture. The col-
orless clear solution was extracted with 10 mL of EtOAc and the
aqueous layer was extracted with 10 mL of EtOAc (ꢁ2). The organic
layers were combined, washed with 5 mL of brine, and dried over
anhydrous Na2SO4. The crude product was chromatographed on
silica gel with a 15:1 mixture of CHCl3 and MeOH to afford 146
mg (82% yield) of (2S,3S)-(+)-N-hydroxy-2,3-methano-3-phenyl-
(CON); HRMS (ESI-TOF): Calcd for
455.2305, found: 455.2277.
C
27H32N2O3Na (M+Na)+:
4.4.5. Cbz-
139 mg (85%); colorless oil; [a]
25 = +12.9 (c 1.21, MeOH); 1H
D
L-Phe-NMe2 6ae
NMR (400 MHz, CDCl3): d 2.62 (s, 3H, CH3), 2.86 (s, 3H, CH3),
2.93–3.03 (m, 2H, CHCH2C6H5), 4.85–4.91 (m, 1H, CHCH2), 5.06
(d, J = 12.4 Hz, 1H, OCHAC6H5), 5.10 (d, J = 12.4 Hz, 1H, OCHBC6H5),
5.69 (br, 1H, NH), 7.14–7.18, 7.21–7.38 (m, m, 2H, 8H, C6H5 ꢁ2);
13C NMR (100 MHz, CDCl3): d 35.5, 36.8, 40.2, 51.9, 66.8, 127.0,
128.0, 128.1, 128.4, 128.5, 129.4, 136.2, 136.4, 155.6, 171.2; IR
(NaCl, vmax/cmꢀ1) = 3280 (CONH), 1716 (CON), 1639 (CON); HRMS
propanamide 8. (2S,3S)-(+)-8: 146 mg (82%); colorless solid; mp:
18
125–127 °C; [a]
D = +338.1 (c 1.13, CHCl3); 1H NMR (400 MHz,
(ESI-TOF): Calcd for
327.1726.
C
19H23N2O3 (M+H)+: 327.1703, found:
CDCl3): d 1.33–1.37 (m, 1H, cyclopropylCHA), 1.65–1.70 (m, 2H,
cyclopropylCHB, CHC6H5), 2.54–2.59 (m, 1H, CHCO), 7.06–7.11,
7.19–7.23, 7.26–7.30 (m, m, m, 2H, 1H, 2H, C6H5), 8.01 (brs, 1H,
NH), 8.26 (brs, 1H, OH); 13C NMR (100 MHz, CDCl3, few drops of
CD3OD for solubility): d 15.5, 23.0, 24.7, 31.3, 126.2, 126.5, 128.5,
140.3, 171.3; IR (KBr, vmax/cmꢀ1) = 3361 (CONH), 3186 (OH),
1653 (CON); HRMS (ESI-TOF): Calcd for C10H11NO2Na (M+Na)+:
200.0682, found: 200.0655.
4.4.6. Cbz-
L-Phe-NEt2 6af
128 mg (72%); colorless oil; [
a]
25 = ꢀ8.7 (c 0.99, MeOH); 1H
D
NMR (400 MHz, CDCl3): d 0.98 (t, J = 7.1 Hz, 3H, CH3), 1.04 (t, J =
7.1 Hz, 3H, CH3), 2.88–3.11 (m, 5H, CH2CH3 ꢁ2, CHCHAC6H5),
3.49–3.58 (m, 1H, CHCHBC6H5), 4.76–4.82 (m, 1H, CHCH2), 5.05
(d, J = 12.3 Hz, 1H, OCHAC6H5), 5.12 (d, J = 12.3 Hz, 1H, OCHBC6H5),
5.61 (br, 1H, NH), 7.18–7.29, 7.30–7.37 (m, m, 5H, 5H, C6H5 ꢁ2);
13C NMR (100 MHz, CDCl3): d 12.8, 14.1, 40.4, 40.5, 41.6, 51.9,
66.8, 127.0, 128.0, 128.1, 128.4, 128.5, 129.6, 136.3, 136.4, 155.6,
170.5; IR (NaCl, vmax/cmꢀ1) = 3273 (CONH), 1716 (CON), 1631
(CON); HRMS (ESI-TOF): Calcd for C21H27N2O3 (M+H)+: 355.2016,
found: 355.2022.
4.6. Typical procedure for the Lossen rearrangment of (2S,3S)-
(+)-N-hydroxy-2,3-methano-3-phenylpropanamide 8
To a colorless solution of 100 mg (0.565 mmol) of (2S,3S)-(+)-N-
hydroxy-2,3-methano-3-phenylpropanamide 8 and 142 mg (0.622
mmol, 1.1 equiv) of 4-nitrobenzenesulfonyl chloride in 5 mL of
anhydrous THF was added 250
NEt at 0 °C. After stirring for 2 h at 0 °C, 9
equiv) of N-methylimidazole and 293 L (2.82 mmol, 5.0 equiv)
l
L (1.41 mmol, 2.5 equiv) of i-Pr2-
4.4.7. Cbz-
L
-Phe-piperidyl 6ag
lL (0.113 mmol, 0.2
154 mg (84%); pale orange oil; [
a]
25 = +2.5 (c 1.01, MeOH); 1H
l
D
NMR (400 MHz, CDCl3): d 0.97–1.04 (m, 1H, piperidylCHACH2CH2N),
1.34–1.58 (m, 5H, piperidyl CHBCH2CH2N, piperidylCH2CH2N ꢁ2),
2.97 (br, 1H, piperidylCHAN), 2.99 (br, 1H, piperidylCHBN), 3.00
(dd, J = 7.3, 13.3 Hz, 1H, CHCHAC6H5) 3.23 (dd, J = 7.3, 13.3 Hz,
1H, CHCHAC6H5) 3.48 (t, J = 5.3 Hz, 2H, piperidylCH2N), 4.91 (ddd,
J = 7.3, 7.3, 8.2 Hz, 1H, CHCH2), 5.06 (d, J = 12.4 Hz, 1H, OCHAC6H5),
5.11 (d, J = 12.4 Hz, 1H, OCHBC6H5), 5.73 (d, J = 8.2 Hz, 1H, NH),
7.13–7.38 (m, 10H, C6H5 ꢁ2); 13C NMR (100 MHz, CDCl3): d 24.3,
25.3, 25.9, 40.2, 43.1, 46.6, 51.4, 66.7, 126.9, 128.0, 128.1, 128.5,
128.5, 129.6, 136.2, 136.5, 155.6, 169.3; IR (NaCl, vmax/cmꢀ1) =
3280 (CONH), 1716 (CON), 1630 (CON); HRMS (ESI-TOF): Calcd
for C22H26N2O3Na (M+Na)+: 389.1836, found: 389.1808.
of benzylalcohol were added to the resulted mixture. The mixture
was stirred for 15 h at 35 °C, diluted with 15 mL of EtOAc, and
washed with 10 mL of half brine. The aqueous layer was extracted
with 10 mL of EtOAc. The organic layers were combined and dried
over anhydrous MgSO4. The crude product was chromatographed
on silica gel with a 4:1 mixture of hexane and EtOAc to afford
131 mg (87% yield) of (1S,2R)-(+)-N-Cbz-tranylcypromine 9.
(1S,2R)-(+)-9: 131 mg (87%); colorless solid; mp: 67–69 °C; [a 27
] =
D
+69.6 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.12–1.27 (m,
1H, cyclopropylCH2), 2.05–2.12 (m, 1H, CHCHC6H5), 2.72–2.81
(m, 1H, CHCO), 5.09 (brs, 1H, NH), 5.12 (s, 2H, OCH2C6H5), 7.10–
7.41 (m, 10H, C6H5 ꢁ2); 13C NMR (100 MHz, CDCl3): d 16.1, 25.1,