Z. Szakonyi et al. / Tetrahedron xxx (2015) 1e7
5
warmed to room temperature and partitioned between Et
3ꢂ200 mL) and brine, and the organic phase was dried (Na SO
and concentrated in vacuo. Purification by column chromatography
on silica gel (R O¼19:1) gave 6.10 g (81%) of the
¼0.6, n-hexane/Et
desired product 7 as a colourless oil.
2
O
pressure and the residue was purified by flash column chroma-
tography on silica gel (R
ane/EtOAc¼9:1), resulting in colourless oily products 10a and 10b.
(
2
4
)
f
¼0.3 for 10a and R ¼0.35 for 10b, n-hex-
f
f
2
4.9.1. (1S,2R,3R,6S)-Methyl 7,7-dimethyl-2-nitromethylbicyclo[4.1.0]
heptane-3-carboxylate (10a). Compound 10a: a colourless oil;
20
Compound 7: [
a
]
D
¼ꢀ5.0 (c 0.25, MeOH); IR (KBr):
n
max 2937,
ꢀ
1 1
20
1
724, 1454, 1365, 1149, 746, 698 cm . H NMR (400.1 MHz, CDCl
3
)
100 mg (74%); [
a
]
D
¼ꢀ2.0 (c 0.25, MeOH); IR (KBr):
n
max 2953, 1735,
ꢀ
1 1
d
0.61 (dd, J¼7.3, 8.8 Hz, 1H), 0.71e0.77 (m, 1H), 0.74 (s, 3H), 1.05 (s,
1154, 1377, 1166 cm . H NMR (400.1 MHz, CDCl ) d
3
0.48 (dd, J¼5.0,
3
H), 1.09e1.21 (m, 1H), 1.44 (s, 9H), 1.58e1.78 (m, 3H), 2.31 (dt,
9.2 Hz, 1H), 0.66 (dt, J¼2.6, 9.5 Hz, 1H), 0.99 (s, 3H), 1.00 (s, 3H),
1.27e1.42 (m, 1H), 1.65e1.73 (m, 1H), 1.78e1.88 (m, 2H), 2.07 (dt,
J¼3.8, 11.7 Hz, 1H), 2.18e2.29 (m, 1H), 3.68 (s, 3H), 4.38 (dd, J¼8.9,
J¼3.6, 11.7 Hz, 1H), 2.76 (dd, J¼4.0, 11.5 Hz, 1H), 3.42 (d, J¼13.5 Hz,
13
2
(
(
5
1
H), 3.91 (d, J¼13.5 Hz, 2H), 7.17e7.39 (m, 10H). C NMR
100.6 MHz, CDCl 15.1 (CH), 17.2 (C ), 18.9 (CH ), 19.5 (CH ), 20.2
CH ), 27.4 (CH ), 29.2 (CH ), 45.9 (CH), 54.3 (CH ),
), 28.3 (3ꢂCH
4.9 (CH), 79.8 (C ), 126.9 (CH Ar), 128.0 (CH Ar), 129.4 (CH Ar),
39.9 (C Ar), 175.5 (C ). Anal. Calcd for C28 : C, 80.15; H,
.89; N, 3.34. Found: C, 79.84; H, 8.59; N, 3.01.
13
3
)
d
q
2
3
11.9 Hz, 1H), 4.52 (dd, J¼4.2, 11.9 Hz, 1H). C NMR (100.6 MHz,
3
2
3
3
2
CDCl
(CH ), 28.9 (CH), 33.2 (CH), 42.4 (CH), 52.0 (CH
(C ). Anal. Calcd for C12 : C, 59.73; H, 7.94; N, 5.81. Found: C,
59.43; H, 7.64; N, 5.51.
3
)
d
15.5 (CH), 18.1 (CH
2
), 19.7 (CH
3
), 23.3 (CH
3
), 26.1 (C
q
), 27.1
q
2
3
), 80.2 (CH
2
), 175.8
q
q
H
37NO
2
q
H19NO
4
8
4
.7. (1R,2R,3R,6S)-tert-Butyl 2-amino-7,7-dimethylbicyclo
4.9.2. (1S,2S,3S,6S)-Methyl 7,7-dimethyl-2-nitromethylbicyclo[4.1.0]
[
4.1.0]heptane-3-carboxylate (8)
heptane-3-carboxylate (10b). Compound 10b: a colourless oil;
2
0
1
0 mg (7%); [
a
]
D
¼ꢀ8.0 (c 0.25, MeOH); IR (KBr):
n
max 2954, 1732,
0.55 (dd, J¼6.0,
ꢀ
1 1
A solution of amino ester 7 (4.60 g, 11.0 mmol) in dry MeOH
1554, 1378, 1173 cm . H NMR (400.1 MHz, CDCl
3
)
d
(
(
20 mL) was added to a suspension of 10% Pd/C (1.10 g) in dry MeOH
100 mL) and the resulting mixture was stirred under H (1 atm) at
2
9.4 Hz, 1H), 0.65 (dt, J¼1.9, 8.6 Hz, 1H), 0.96 (s, 3H), 1.00 (s, 3H),
1.28e1.40 (m, 1H), 1.47e1.55 (m, 1H), 1.77e1.88 (m, 1H), 1.98e2.07
(m, 1H), 2.10e2.18 (m, 1H), 2.55 (q, J¼4.3, 8.5 Hz, 1H), 3.70 (s, 3H),
room temperature for 12 h. The solution was filtered through a pad
of Celite, and the solvent was removed. The crude oily product
obtained was dissolved in DCM (200 mL) and was washed with 10%
13
4.72 (ddd, J¼4.3, 8.2, 12.4 Hz, 2H). C NMR (100.6 MHz, CDCl
3
)
d
15.1 (CH), 15.5 (CH
2
), 19.4 (CH
3
), 22.8 (CH
), 80.2 (C
4
H19NO : C, 59.73; H, 7.94; N, 5.81. Found: C, 59.43; H,
3
), 26.2 (CH
2
), 28.7 (CH
2
),
NaOH solution (50 mL). The organic phase was dried with Na
filtered and concentrated in vacuo before purification via column
chromatography on silica gel (R
¼0.3, toluene/EtOH¼4:1), affording
.36 g (90%) of colourless oily product 8.
2
SO
4
,
29.9 (C ), 33.6 (CH), 39.4 (CH), 51.7 (CH
Calcd for C12
7.64; N, 5.51.
q
3
q
), 175.6 (C
q
). Anal.
f
2
2
0
Compound 8: [
a]
D
¼ꢀ14.0 (c 0.25, MeOH); IR (KBr):
n
max 2941,
0.43 (dd,
4.10. (1S,2R,3R,6S)-Methyl 2-aminomethyl-7,7-
dimethylbicyclo[4.1.0]heptane-3-carboxylate hydrochloride
(11)
ꢀ
1 1
1
720, 1369, 1314, 1147 cm . H NMR (400.1 MHz, CDCl
3
)
d
J¼3.7, 9.2 Hz, 1H), 0.61 (t, J¼8.3 Hz, 1H), 0.97 (s, 3H), 1.02 (s, 3H),
1
.11e1.20 (m, 1H), 1.43 (s, 9H), 1.62e1.69 (m, 1H), 1.72e1.86 (m, 3H),
13
2
.71 (dd, J¼3.6, 11.0 Hz, 1H). C NMR (100.6 MHz, CDCl
), 17.5 (C ), 18.5 (CH ), 20.2 (CH), 26.6 (CH
CH), 29.3 (CH ), 47.6 (CH), 51.1 (CH), 80.4 (C
3
)
d
15.7
), 29.2
). Anal.
: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.74; H,
Nitro ester 10a (100 mg, 0.41 mmol) was dissolved in 15 mL of
dry MeOH and hydrogenated with H gas at atmospheric pressure
2
over Raney Ni (80 mg) for 2 h. The mixture was then filtered, the
filtrate was evaporated, and the product was purified by column
(
(
CH
3
q
2
2
), 28.3 (3ꢂCH
3
3
q
), 176.1 (C
q
Calcd for C14
H
25NO
2
8
.30; N, 4.51.
chromatography (silica gel, R
amino ester, which was purified as hydrochloride 11 by re-
crystallization from EtOH/Et O.
Compound 11: white crystals; 53 mg (52%); mp 198e201 C;
f
¼0.5, toluene/EtOH¼1:1), giving the
4
.8. (1R,2R,3R,6S)-2-Amino-7,7-dimethylbicyclo[4.1.0]hep-
2
ꢁ
tane-3-carboxylic acid hydrochloride (9)
2
0
[a
]
D
¼ꢀ13.0 (c 0.25, MeOH); IR (KBr):
n
max 2950, 1735, 1438, 1315,
ꢀ
1 1
Amino ester 8 (10 mmol) was dissolved in a mixture of Et
2
O
1164 cm . H NMR (400.1 MHz, DMSO-d 0.52e0.66 (m, 2H),
6
) d
(
15 mL) and 10% aqueous HCl solution (100 mL). The mixture was
0.95 (s, 3H), 1.02 (s, 3H), 1.10e1.25 (m, 1H), 1.55e1.86 (m, 4H), 1.98
(dt, J¼4.2, 11.6 Hz, 1H), 2.68e2.88 (m, 2H), 3.62 (s, 3H), 8.24 (br s,
then stirred at room temperature for 24 h and subsequently
evaporated to dryness, and the resulting white crystalline product 9
was washed with Et
from EtOH/Et
13
3H). C NMR (100.6 MHz, DMSO-d
6
)
d
15.4 (CH
), 28.7 (CH
). Anal. Calcd for C12
3
), 17.4 (C
), 31.7 (CH), 42.3
22ClNO
q
), 17.6
2
O, filtered off and purified by recrystallization
(CH
(CH), 42.9 (CH
2
), 18.8 (CH), 21.5 (CH), 26.1 (CH
), 51.6 (CH ), 175.7 (C
2
3
2
O, resulting in 0.82 g (44%) product.
Compound 9: white crystals; mp 214e216 C; [
2
3
q
H
2
:
ꢁ
20
a
]
D
¼ꢀ13.0 (c
C, 58.17; H, 8.95; N, 5.65. Found: C, 57.87; H, 8.65; N, 5.35.
ꢀ
1 1
0
.25, MeOH); IR (KBr):
NMR (400.1 MHz, DMSO-d
H), 0.96 (s, 3H), 1.04 (s, 3H), 1.14e1.25 (m, 1H), 1.50e1.61 (m, 1H),
n
max 2881, 1714, 1509, 1375, 1205 cm . H
6
)
d
0.63e0.71 (m, 1H), 0.77 (t, J¼7.5 Hz,
4.11. (1R,5S,9R)-9-Aminomethyl-4,4-dimethyl-3-oxabicyclo
[3.3.1]nonan-2-one hydrochloride (13)
1
1
8
d
.77e1.92 (m, 2H), 2.24e2.35 (m, 1H), 2.98 (dd, J¼3.1, 10.5 Hz, 1H),
13
.28 (br s, 3H), 12.85 (br s, 1H). C NMR (100.6 MHz, DMSO-d
15.8 (CH ), 18.2 (C ), 18.3 (CH ), 20.5 (CH), 23.9 (CH), 26.4 (CH
9.3 (CH ), 43.6 (CH), 46.7 (CH), 175.9 (C ). Anal. Calcd for
18ClNO : C, 54.67; H, 8.26; N, 6.38. Found: C, 54.34; H, 7.94; N,
.08.
6
)
Amino ester 11 (100 mg, 0.47 mmol) was dissolved in a mixture
of Et O (5 mL) and 15% aqueous HCl solution (15 mL). The mixture
was stirred at room temperature for 12 h, and then evaporated to
dryness, and the resulting white crystalline product 9 was washed
2
with Et O, filtered off and purified by recrystallization from EtOH/
3
q
2
2
),
2
2
C
6
3
q
10
H
2
Et
2
O, resulting in 75 mg (79%) of amino lactone 13.
Compound 13: white crystals; mp 199e202 C; [
ꢁ
20
4
.9. Conjugate addition of MeNO
2
to compound 5
a
]
D
¼þ10.0 (c
1 1
ꢀ
0
.25, MeOH); IR (KBr):
NMR (400.1 MHz, DMSO-d
1.45e1.77 (m, 4H), 1.80e1.92 (m, 2H), 2.60e2.68 (m, 1H), 2.69e2.75
n
max 2873, 1683, 1494, 1333, 1108 cm . H
A mixture of methyl isochaminate (5) (100 mg, 0.56 mmol),
tetra-n-butylammonium bromide (TBAB) (18.1 mg, 0.1 equiv) and
DBU (84 L, 0.56 mmol) in 2 mL of MeNO was heated under reflux
for 20 h. Next, the solvent was evaporated off under reduced
6
) d
1.24e1.37 (m, 1H), 1.40 (s, 6H),
13
m
2
(m, 1H), 2.99e3.15 (m, 2H), 8.22 (br s, 3H). C NMR (100.6 MHz,
DMSO-d 19.5 (CH ), 21.4 (CH ), 24.2 (CH ), 27.1 (CH ), 30.4 (CH ),
6
)
d
2
2
2
3
3