at 0 ЊC and then the reaction mixture was stirred at rt for 5 h.
CH2Cl2 (300 ml) was added and the solution was extracted
with1MHCl(4×100ml), NaHCO3 (sat., 100ml)andwater(100
ml). Purification by flash chromatography (EtOAc–pentane,
1:10 to 1:4) afforded 3 (9.94 g, 74%) as a colourless oil. Rf 0.82
(EtOAc–pentane, 60:40); [α]2D4 ϩ65.5 (c 1.11 in CHCl3); (Found:
C, 59.1; H, 7.2; N, 3.6. Calc. for C19H27NO5S: C, 59.8; H, 7.1;
N, 3.7%); νmax(film)/cmϪ1 1698, 1366, 1177; δH(200 MHz, 1:1
mixture of rotamers) 1.22 (m, 2H), 1.32 (s, 9H), 1.39 (s, 9H),
1.65 (m, 8H), 2.43 (s, 6H), 2.51 (m, 2H), 3.30 (m, 1H), 3.44 (m,
1H), 3.64 (m, 1H), 3.77 (m, 1H), 4.10 (m, 6H), 7.33 (m, 4H),
7.77 (m, 4H); δC(50.2 MHz, 1:1 mixture of rotamers) 21.6, 27.2,
28.3, 28.4, 29.6, 30.1, 33.8, 34.6, 38.6, 39.2, 56.7, 57.6, 61.5,
61.7, 68.4, 68.6, 79.8, 127.9, 129.8, 133.0, 145.2; m/z (EI) 281
(Mϩ – Boc, <1%), 53 (17), 54 (30), 65 (28), 66 (32), 67 (100), 68
(74), 77 (11), 78 (10), 79 (14), 80 (68), 81 (17), 82 (12), 94 (72),
108 (54), 112 (29), 138 (17), 153 (66).
(1S,3R,4R)-3-Benzylsulfinylmethyl-2-azabicyclo[2.2.1]heptane-
2-carboxylic acid tert-butyl ester 6
Compound 4 (0.300 g, 0.9 mmol) was dissolved in MeOH (10
ml) and cooled to 0 ЊC. NaIO4 (0.222 g, 1.04 mmol) was dis-
solved in H2O (5 ml) and added dropwise. The reaction was
stirred for one hour at 0 ЊC then the ice bath was removed and
the reaction was stirred at rt for 3.5 h. The solvent was removed
in vacuo and the residue was extracted with CH2Cl2 (3 × 5 ml).
The combined organic phases were dried (MgSO4) and the sol-
vent was evaporated. Purification of the residue by flash chro-
matography (EtOAc–MeOH, 20:0.3) afforded 6 (0.200 g, 64%)
as a 3:2 mixture of diastereomers, as pale yellow crystals. The
diastereomers were separated on an OD column [hexane–i-
PrOH, 85:15, 6 ml minϪ1, retention times 24 min (major), 33
min (minor)].
Major-6: [α]2D4 ϩ46.2 (c 1.01 in CHCl3); νmax(CDCl3)/cmϪ1
3063, 2973, 2875, 1690, 1392, 1033;δH(400 MHz, mixture of
rotamers) 1.30 (s, 9H), 1.26–1.32 (m, 1H), 1.45 (s, 9H), 1.54–
1.74 (m, 5H), 2.46–2.55 (m, 1H), 2.69–2.74 (m, 1H), 2.79–2.85
(m, 1H), 3.04–3.11 (m, 1H), 3.49–3.54 (m, 1H), 3.62–3.68 (m,
1H), 3.86–3.93 (m, 1H), 4.02–4.08 (m, 1H), 4.11–4.18 (m, 1H),
7.26–7.40 (m, 5H); δC(100.6 MHz, mixture of rotamers) 27.4
28.3, 28.5, 29.8, 30.3, 34.2, 34.9, 41.2, 42.1, 55.2, 56.6, 57.6,
58.9, 60.2, 60.6, 60.7, 128.2, 128.5, 128.7, 129.1, 129.9, 130.3;
m/z (EI) 350 (Mϩ ϩ 1, 20%), 334 (26), 294 (16), 278 (19), 250
(27), 232 (11) 202 (36), 186 (7), 154 (16), 140 (45), 91 (100),
68 (20).
(1S,3R,4R)-3-Benzylsulfanylmethyl-2-azabicyclo[2.2.1]heptane-
2-carboxylic acid tert-butyl ester 4
Toluene-α-thiol (0.882 g, 7.08 mmol) was dissolved in THF (20
ml). The solution was cooled to 0 ЊC and n-BuLi (4.42 ml, 7.08
mmol, 1.6 M in hexanes) was added dropwise via syringe. The
reaction was stirred for 10 min then more n-BuLi was added
until the solution turned deep red. The reaction was stirred for
an additional 40 min. The mixture was added to an ice-cooled
solution of 3 (1.80 g, 4.72 mmol) as a solution in THF (20 ml).
The mixture was stirred at rt overnight. The solvent was evap-
orated and the mixture was extracted with water (30 ml) and
Et2O (30 ml). The water phase was then extracted with Et2O
(2 × 30 ml) and the combined organic phases were dried
(MgSO4) and filtrated. The crude product was purified by
column chromatography (pentane–EtOAc, 10:1) to give 4 (1.00 g,
64%) as a colourless oil. [α]2D4 Ϫ67.0 (c 0.941 in CHCl3); (Found:
C, 68.6; H, 8.3; N, 4.35. Calc. for C19H27NO2S: C, 68.4; H, 8.2;
N, 4.2%); νmax(CDCl3)/cmϪ1 2973, 2873, 1693, 1391, 1175;
δH(400 MHz, 1:1 mixture of rotamers) 1.17 (m, 1H), 1.20 (m,
1H), 1.25–1.76 (m, 15H), 2.17–2.31 (m, 1H), 2.51–2.57 (m, 1H),
2.86 (dd, 1H, J = 13.4, 3.1 Hz), 2.94 (dd, 1H, J = 13.4, 3.1 Hz),
3.18–3.24 (m, 1H), 3.39–3.43 (m, 1H), 3.76 (s, 1H), 3.80 (s, 1H),
4.00–4.04 (m, 1H), 4.11–4.15 (m, 1H), 7.38–7.17 (m, 10H);
δC(100.6 MHz, 1:1 mixture of rotamers) 27.8, 28.7, 28.8, 29.9,
30.5, 34.1, 34.4, 34.8, 35.0, 37.6, 38.5, 39.9, 40.6, 57.3, 58.2,
63.8, 64.1, 79.1, 79.4, 126.8, 127.0, 128.3, 128.5, 128.7, 128.9,
138.3, 138.7, 154.9; m/z (EI) 334 (Mϩ ϩ 1, 100%), 278 (14), 234
(20), 196 (9), 140 (33), 96 (40), 91 (18), 68 (30).
Minor-6: [α]2D4 ϩ91.7 (c 0.86 in CHCl3); νmax(CDCl3)/cmϪ1
2975, 2873, 1691, 1393, 1026; δH(400 MHz, mixture of rotam-
ers) 1.23–1.32 (m, 1H), 1.37 (s, 9H), 1.46 (s, 9H), 1.54–1.64 (m,
1H), 2.32–2.38 (m, 1H), 2.53–2.57 (m, 1H), 2.68–2.74 (m, 1H),
2.89–2.98 (m, 1H), 3.62–3.66 (m, 1H), 3.68–3.73 (m, 1H), 3.98–
4.05 (m, 1H), 4.08 (m, 1H), 4.16 (m, 1H), 4.29–4.33 (m, 1H),
7.25–7.41 (m, 5H); δC(100.6 MHz, mixture of rotamers) 27.4,
28.4, 28.5, 29.6, 30.1, 34.1, 35.0, 40.8, 41.5, 54.1, 54.7, 56.8,
57.8, 57.8, 57.9, 58.6, 128.1, 128.4, 128.7, 128.9, 130.1, 130.3;
m/z (EI) 350 (Mϩ ϩ 1, 20%), 334 (26), 294 (16), 278 (19), 250
(27), 232 (11) 202 (36), 186 (7), 154 (16), 140 (45), 91 (100), 68
(20).
(1S,3R,4R)-3-Benzylsulfinylmethyl-2-azabicyclo[2.2.1]heptane:
major-7
Use of the same procedure as reported for 5 using major-6
(0.120 g, 0.36 mmol) and TFA (1.25 ml), afforded major-7
(0.0801 g, 94%) as white crystals. [α]2D4 Ϫ163.2 (c 0.95 in CHCl3);
νmax(CDCl3)/cmϪ1 3435, 2960, 2897, 1640, 1023; δH(400 MHz)
1.20–1.24 (m, 1H), 1.30–1.49 (m, 2H), 1.53–1.71 (m, 3H), 1.83
(br s, 1H), 2.24 (m, 1H), 2.43 (dd, 1H, J = 12.2, 10. 1 Hz), 2.57
(dd, 1H, J= 12.2, 3.6 Hz), 3.49 (m, 1H), 3.95 (d, 1H, J = 13.1
Hz), 3.97 (d, 1H, J = 13.1 Hz), 7.27–7.38 (m, 5H); δC(100.6
MHz) 28.7, 32.9, 34.3, 41.4, 54.9, 56.4, 58.7, 59.4, 128.2, 128.8,
130.0, 130.1; m/z (EI) 250 (Mϩ ϩ 1, 59%), 232 (15), 197 (25),
185 (15), 140 (19), 109 (74), 91 (100), 68 (94).
(1S,3R,4R)-3-Benzylsulfanylmethyl-2-azabicyclo[2.2.1]heptane
5
Compound 4 (0.820 g, 0.36 mmol) was dissolved in CH2Cl2
(16 ml) and cooled to 0 ЊC after which TFA (8.2 ml) was added
dropwise. The ice bath was removed and the reaction mixture
was stirred at rt for 2 h. The solvent and TFA were then evapor-
ated off in vacuo. The residue was dissolved in CH2Cl2 (5 ml)
and K2CO3 was added until no evolution of CO2 (g) could be
seen. The solution was filtred through Celite and extracted with
2 M HCl (10 ml), and the water phase was made basic (pH 9–
10) by addition of 2 M NaOH, and extracted with CH2Cl2
(3 × 10 ml). The combined organic phases were dried (MgSO4),
filtered through Celite and evaporated. Purification by flash
chromatography (CH2Cl2–MeOH, 100:0 to 80:20) yielded 5
(0.399 g, 70%) as a pale yellow oil. [α]2D4 Ϫ32.6 (c 0.276 in
CHCl3); νmax(CDCl3)/cmϪ1 3392, 2944, 2861, 1600, 1412; δH(400
MHz) 1.12–1.16 (m, 1H), 1.30 (m, 1H), 1.47–1.51 (m, 1H),
1.52–1.68 (m, 1H), 2.28 (m, 1H), 2.38–2.22 (m, 3H), 2.73
(m, 1H), 3.42 (m, 1H), 3.72 (s, 2H), 7.35–7.15 (m 5H); δC(100.6
MHz) 28.8, 32.6, 34.3, 36.6, 38.3, 40.5, 56.2, 60.7, 126.9, 128.4,
128.8, 138.6; m/z (EI) 234 (Mϩ ϩ 1, 15%), 223 (9), 123 12), 96
(61), 91 (51), 68 (100).
(1S,3R,4R)-3-Benzylsulfinylmethyl-2-azabicyclo[2.2.1]heptane:
minor-7
Use of the same procedure as reported for 5 using minor-6
(0.130 g, 0.39 mmol) and TFA (1.25 ml) yielded minor-7
(0.0534 g, 58%) as white crystals. [α]2D4 ϩ57.4 (c 0.35 in CHCl3);
νmax(CDCl3)/cmϪ1 3400, 3031, 2960, 2873, 1685, 1201, 1026;
δH(400 MHz) 1.27 (m, 1H), 1.47 (m, 2H), 1.49 (m, 1H), 1.63 (m,
3H), 1.8 (br s), 2.35 (m, 1H), 2.54 (dd, 1H, J = 13.1, 8.0 Hz),
2.79 (dd, 1H, J = 13.1, 6.1 Hz), 3.25–3.62 (m, 3H), 4.08 (s, 2H),
7.20–7.42 (m, 5H); δC(100.6 MHz) 28.7, 32.9, 34.3, 41.4, 54.9,
56.4, 58.7, 59.4, 128.2, 128.8, 130.0, 130.1; m/z (EI) 250 (Mϩ ϩ
1, 58%), 232 (10), 197 (25), 185 (15), 140 (19), 109 (33), 91 (100),
68 (69).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
362