A. Ruffoni et al. / Tetrahedron 68 (2012) 1951e1962
1959
4.6.1. (1R
*
,2R
*
,3S
*
,4S
*
)-Ethyl 2-amino-3-(phenylthio)bicyclo[2.2.1]
1H, 3-H) 2.72 (br s,1H,1-H), 2.33e2.25 (m, 2H, 4-H, 7a-H),1.84 (br s,
2H, NH2), 1.68e1.61 (m, 1H, 7b-H), 1.38e1.30 (m, 3H, CH3) ppm; 13
NMR (75.4 MHz, CDCl3, 25 ꢀC)
(CePh), 136.3 (C-6), 129.2, 128.7, 127.3 (CHePh), 70.7 (CH2), 61.6 (C-
2), 60.1 (C-3), 51.8 (C-1), 50.8 (C-4), 49.3 (C-7), 38.5 (CH2), 14.4
(CH3) ppm; MS (ESI): m/z¼304.2 [MþH]þ. C17H21NO2S (303.1):
calcd C, 67.29; H, 6.98; N, 4.62; found C, 66.99; H, 6.89; N, 4.40.
hept-5-ene-2-carboxylate (exo-13a). Yellow oil; flash chromatog-
raphy (eluent 300:100:3.2) cyclohexane/AcOEt/TEA; yield 88%;
C
d
¼174.2 (CO), 139.4 (C-5), 138.2
Rf¼0.12 (2:1 hexane/AcOEt); IR (NaCl):
n
¼3392, 2981, 1728,
1185 cmꢂ1; 1H NMR (300 MHz, CDCl3, 25 ꢀC):
d
¼7.40e7.20 (m, 5H,
Ph), 6.45e6.30 (m, 2H, 5-H, 6-H), 4.20 (m, 2H, CH2), 3.10 (m, 1H, 1-
H), 2.95 (br s, 1H, 4-H), 2.90 (d, J¼3.0 Hz, 1H, 3-H), 2.40 (d,
J7a,7b¼9.5 Hz,1H, 7a-H),1.90 (br s, 2H, NH2),1.76e1.70 (m,1H, 7b-H),
13
1.20 (t, J¼7.1 Hz, 3H, CH3) ppm; C NMR (75.4 MHz, CDCl3, 25 ꢀC)
4.6.6. (1R
*
,2R
*
,3R
*
,4S )-Ethyl 2-amino-3-(benzylthio)bicyclo[2.2.1]
*
d
¼173.3 (CO), 139.3 (C-5), 136.6 (C-6), 137.3 (CePh), 130.1, 129.1,
hept-5-ene-2-carboxylate (exo-130b). Yellow oil; flash chromatog-
raphy n-hexane/AcOEt/TEA (600:100:5.6); yield 70%; Rf¼0.3 (2:1
126.5 (CHePh), 70.2 (CH2), 63.1 (C-3), 61.6 (C-2), 52.1 (C-1), 51.0 (C-
4), 49.1 (C-7), 14.1 (CH3) ppm; MS (ESI): m/z¼290.1 [MþH]þ.
C16H19NO2S (289.1): calcd C, 66.41; H, 6.62; N, 4.84; found C, 66.22;
H, 6.12; N, 4.32.
hexane/AcOEt); IR (NaCl):
(300 MHz, CDCl3, 25 ꢀC):
n
¼3380, 2978, 1724, 1239 cmꢂ1; 1H NMR
d¼7.36e7.21 (m, 5H, Ph), 6.34e6.30 (m,
1H, 5-H), 6.28e6.23 (m, 1H, 6-H), 4.25e4.12 (m, 2H, CH2), 3.72 (br s,
2H, CH2), 3.66 (d, J¼3.3 Hz, 1H, 3-H) 3.15 (br s, 1H, 1-H), 2.94 (br s,
1H, 4-H), 1.69 (d, Ja,b¼9.3 Hz, 1H, 7a-H), 1.59 (br s, 2H, NH2), 1.48 (d,
Jb,a¼9.3 Hz, 1H, 7b-H), 1.31e1.24 (m, 3H, CH3) ppm; 13C NMR
4.6.2. (1R
*
,2S
*
,3R
*
,4S )-Ethyl 2-amino-3-(phenylthio)bicyclo[2.2.1]
*
hept-5-ene-2-carboxylate (endo-13a). Yellow oil; flash chromatog-
raphy cyclohexane/AcOEt/TEA (300:100:3.2); yield 88%; Rf¼0.26
(75.4 MHz, CDCl3, 25 ꢀC)
d¼175.6 (CO), 138.8 (CePh), 138.0 (C-5),
(2:1 hexane/AcOEt); IR (NaCl):
NMR (300 MHz, CDCl3, 25 ꢀC):
n
¼3369, 2979, 1731, 1258 cmꢂ1
;
1H
135.9 (C-6), 129.1, 128.7, 127.2 (CHePh), 66.7 (CH2), 61.6 (C-2), 56.3
(C-3), 52.9 (C-1), 48.7 (C-4), 47.0 (C-7), 37.4 (CH2), 14.3 (CH3) ppm;
MS (ESI): m/z¼304.2 [MþH]þ. C17H21NO2S (303.1): calcd C, 67.29;
H, 6.98; N, 4.62; found C, 67.43; H, 7.07; N, 4.55.
d
¼7.45e7.10 (m, 5H, Ph), 6.50 (dd,
J¼3.1 Hz, J5,6¼5.6 Hz,1H, 5-H), 6.30 (dd, J¼3.0 Hz, J6,5¼5.6 Hz,1H, 6-
H), 4.23e3.95 (m, 2H, CH2), 3.70 (d, J¼3.5 Hz,1H, 3-H), 3.10 (br s,1H,
1-H), 2.90 (br s, 1H, 4-H), 2.15 (d, J7a,7b¼8.9 Hz, 1H, 7a-H), 2.10 (br s,
2H, NH2), 1.63e1.58 (m, 1H, 7b-H), 1.10 (t, J¼7.2 Hz, 3H, CH3) ppm;
4.6.7. (1R
*
,2S
*
,3S
*
,4S
*
)-Ethyl
2-amino-3-(benzylthio)bicyclo[2.2.1]
13C NMR (75.4 MHz, CDCl3, 25 ꢀC)
d
¼173.5 (CO), 138.8 (C-5), 137.9
hept-5-ene-2-carboxylate (endo-130b). White wax; flash chroma-
tography n-hexane/AcOEt/TEA (600:100:5.6); yield 76%; Rf¼0.47
(CePh), 134.3 (C-6), 129.8, 128.9, 126.2 (CHePh), 71.6 (CH2), 63.2 (C-
3), 61.2 (C-2), 53.9 (C-1), 48.6 (C-4), 47.2 (C-7), 14.1 (CH3) ppm; MS
(ESI): m/z¼290.1 [MþH]þ. C16H19NO2S (289.1): calcd C, 66.41; H,
6.62; N, 4.84; found C, 66.14; H, 6.30; N, 4.63.
(2:1 hexane/AcOEt); IR (NaCl):
NMR (300 MHz, CDCl3, 25 ꢀC):
n
¼3370, 2921, 1704, 1252 cmꢂ1
;
1H
d
¼7.36e7.20 (m, 5H, Ph), 6.14 (dd,
J¼3.3 Hz, J5,6¼5.6 Hz, 1H, 5-H), 5.98 (dd, J¼2.9 Hz, J6,5¼5.6 Hz, 1H,
6-H), 4.14e4.03 (m, 2H, CH2), 3.80 (br s, 2H, CH2) 3.25 (d, J¼2.2 Hz,
1H, 3-H), 2.75 (br s, 1H, 1-H), 2.66 (br s, 1H, 4-H), 2.04 (d,
J7a,7b¼9.2 Hz,1H, 7a-H),1.69 (br s, 2H, NH2),1.59e1.56 (m,1H, 7b-H),
4.6.3. (1R
*
,2R
*
,3R
*
,4S )-Ethyl 2-amino-3-(phenylthio)bicyclo[2.2.1]
*
hept-5-ene-2-carboxylate (exo-130a). Yellow oil; flash chromatog-
raphy cyclohexane/AcOEt/TEA (500:100:4.2); yield 89%; Rf¼0.34
13
1.25e1.18 (m, 3H, CH3) ppm; C NMR (75.4 MHz, CDCl3, 25 ꢀC)
(1:1 hexane/AcOEt); IR (NaCl):
NMR (300 MHz, CDCl3, 25 ꢀC):
n
¼3381, 2979, 1726, 1240 cmꢂ1
;
1H
d
¼174.1 (CO), 137.9 (CePh), 137.5 (C-5), 134.2 (C-6), 128.2, 127.8,
d
¼7.55e7.05 (m, 5H, Ph), 6.50 (dd,
126.3 (CHePh), 64.7 (CH2), 60.2 (C-2), 52.8 (C-3), 51.9 (C-1), 49.3 (C-
4), 45.0 (C-7), 37.1 (CH2), 13.5 (CH3) ppm; MS (ESI): m/z¼304.2
[MþH]þ. C17H21NO2S (303.1): calcd C, 67.29; H, 6.98; N, 4.62; found
C, 66.92; H, 6.85; N, 4.45.
J¼2.9 Hz, J5,6¼5.6 Hz,1H, 5-H), 6.35 (dd, J¼3.1 Hz, J6,5¼5.6 Hz,1H, 6-
H), 4.30 (d, J¼3.4 Hz, 1H, 3-H), 4.20 (q, J¼7.2 Hz, 2H, CH2), 3.20 (br s,
1H, 1-H), 3.15 (br s, 1H, 4-H), 1.84e1.80 (m, 3H, 7a-H, NH2),
1.59e1.53 (m, 1H, 7b-H), 1.25 (t, J¼7.2 Hz, 3H, CH3) ppm; 13C NMR
(75.4 MHz, CDCl3, 25 ꢀC)
d
¼175.3 (CO), 138.1 (C-5), 136.7 (CePh),
4.7. General procedure for the hydrolysis reaction of (exo-
130a,b), (exo-160a,b) and (endo-160a,b)
136.1 (C-6), 130.5, 129.1, 126.6 (CHePh), 67.1 (CH2), 61.7 (C-2), 58.9
(C-3), 53.2 (C-1), 48.8 (C-4), 46.7 (C-7),14.3 (CH3) ppm; MS (ESI): m/
z¼290.1 [MþH]þ. C16H19NO2S (289.1): calcd C, 66.41; H, 6.62; N,
4.84; found C, 66.56; H, 6.70; N, 4.50.
The appropriate amine (1 equiv) was dissolved in a solution of
aqueous HCl (0.06 M) in a sealed Pyrex tube. The solution was
heated at 100 ꢀC for 6 h, with magnetic stirring, and monitoring by
H NMR spectroscopy. The solution was filtered and the solvent was
evaporated under reduced pressure to give pure product. The re-
actions were performed on the 0.1e0.5 mmol scale. Yields are re-
ported below.
4.6.4. (1R
*
,2S
*
,3S
*
,4S )-Ethyl 2-amino-3-(phenylthio)bicyclo[2.2.1]
*
hept-5-ene-2-carboxylate (endo-130a). Yellow oil; flash chroma-
tography cyclohexane/AcOEt/TEA (500:100:4.2); yield 89%; Rf¼0.51
(1:1 hexane/AcOEt); IR (NaCl):
NMR (300 MHz, CDCl3, 25 ꢀC):
n
¼3378, 2979, 1727, 1232 cmꢂ1
;
1H
d
¼7.50e7.15 (m, 5H, Ph), 6.20 (dd,
J¼3.2 Hz, J5,6¼5.6 Hz, 1H, 5-H), 6.05 (dd, J¼3.0 Hz, J6,5¼5.6 Hz, 1H,
6-H), 4.22e4.08 (m, 2H, CH2), 3.75 (d, J¼2.3 Hz, 1H, 3-H), 2.90 (br s,
1H, 1-H), 2.85 (br s, 1H, 4-H), 2.25 (d, J7a,7b¼9.0 Hz, 1H, 7a-H), 2.00
4.7.1. (1R
5-en-2-aminium chloride (exo-140a). Off-white solid; yield 85%;
mp: 210 ꢀC decomposition (MeOH/Et2O); IR (KBr):
¼3436, 2859,
1734 cmꢂ1 1H NMR (300 MHz, D2O, 25 ꢀC):
¼7.25e7.13 (m, 5H,
*
,2R
*
,3R
*
,4S )-2-Carboxy-3-(phenylthio)bicyclo[2.2.1]hept-
*
n
(br s, 2H, NH2), 1.70 (d, J7b,7a¼9.0 Hz, H 1, 7b-H), 1.25 (t, J¼7.1 Hz, 3H,
;
d
13
CH3) ppm; C NMR (75.4 MHz, CDCl3, 25 ꢀC)
d¼174.4 (CO), 138.4
Ph), 6.52 (dd, J¼2.9, 5.5 Hz, 1H, 5-H), 6.25 (dd, J¼2.9, 5.5 Hz, 1H, 6-
H), 4.45 (d, J¼3.1 Hz, 1H, 3-H), 3.29 (br s, 1H, 1-H), 3.25 (br s, 1H, 4-
(C-5), 137.1 (CePh), 135.3 (C-6), 130.6, 129.1, 126.6 (CHePh), 66.1
(CH2), 61.3 (C-2), 55.4 (C-3), 53.6 (C-1), 50.7 (C-4), 46.1 (C-7), 14.3
(CH3) ppm; MS (ESI): m/z¼290.1 [MþH]þ. C16H19NO2S (289.1):
calcd C, 66.41; H, 6.62; N, 4.84; found C, 66.19; H, 6.39; N, 4.56.
H), 2.03 (d, J7a,7b¼9.8 Hz, 1H, 7a-H), 1.61e1.55 (dd, J¼1.8, 9.8 Hz, 1H,
13
7b-H); C NMR (75.4 MHz, D2O, 25 ꢀC)
d
¼173.7 (CO), 140.7 (C-5),
135.0 (C-6), 133.8 (CePh), 130.0, 129.7, 127.8 (CHePh), 67.4 (C-2),
55.2 (C-3), 52.6 (C-1), 49.4 (C-4), 47.3 (C-7) ppm; MS (ESI): m/
z¼262.1 [MþH]þ. C14H16ClNO2S (297.0): calcd C, 56.46; H, 5.42; N,
4.70; found C, 56.67; H, 5.51; N, 4.98.
4.6.5. (1R
*
,2R
*
,3S
*
,4S )-Ethyl 2-amino-3-(benzylthio)bicyclo[2.2.1]
*
hept-5-ene-2-carboxylate (exo-13b). Off-white oil. Obtained in pure
form without column chromatography. Yield 90%; Rf¼0.13 (2:1
hexane/AcOEt); IR (NaCl):
(300 MHz, CDCl3, 25 ꢀC):
n
¼3391, 2980, 1723, 1244 cmꢂ1; 1H NMR
4.7.2. (1S
*
,2R
*
,3R
*
,4R )-2-Carboxy-3-(phenylthio)bicyclo[2.2.1]hep-
*
d
¼7.36e7.19 (m, 5H, Ph), 6.32e6.23 (m,
tan-2-aminium chloride (exo-150a). White solid; yield 90%; mp:
2H, 5-H, 6-H), 4.35e4.18 (m, 2H, CH2), 3.81 (s, 2H, CH2), 3.02 (br s,
285e286 ꢀC (MeOH/Et2O); IR (KBr):
n
¼3414, 2877, 1714 cmꢂ1
;
1H