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Chemistry - A European Journal
Supporting Information
for
Highly Diastereoselective and Enantioselective Preparation of Homoallylic
Amines. Application for the Synthesis of
Ȳ
-Amino Acids and g-Lactams.
P. Veeraraghavan Ramachandran and Thomas E. Burghardt
Experimental procedures and spectral data
Preparation of
N
-silylimines,
N
-aluminoimines, and all
'allyl'boration reactions were carried out under nitrogen
atmosphere. THF was distilled from sodium benzophenone
ketyl prior to use; all other chemicals and solvents were
purchased commercially and used without further
purification; (–)-
B
-allyldiisopinocampheylborane (
I
) was
prepared according to Brown's procedure by the treatment
of (–)-B-methoxydiisopinocampheylborane with
allylmagnesium bromide. The NMR chemical shifts (
Ō
) are
reported in ppm.
NH
2
To a solution of benzonitrile (
3a;
0.52 mL,
5.05 mmol) in Et
2
O (5 mL) cooled to 0 ºC was added
DIBAL-H (0.89 mL, 5.0 mmol) and the mixture was stirred
for 1 h. The obtained
N
-aluminoimine (
4a;
1
H NMR (300
MHz, CDCl
3
,
Ō
): 0.14-0.19 (m, 3H), 0.76-1.07 (m, 12H),
1.79 (m qn,
J =
6.6 Hz, 3H), 7.48-7.80 (m, 5H), 9.00 (s,
1H);
13
C NMR (75 MHz, CDCl
3
,
Ō
): 22.7, 22.8, 26.3, 26.5,
28.2, 28.3, 28.5, 28.7, 129.4, 129.5, 132.4, 132.8, 133.0,
137.1, 174.5, 175.0) was transferred
via
canula to a solution
of
I
(1 M in pentane; 6 mL, 6 mmol) diluted with Et
2
O (7
mL) and cooled to –100 °C, followed by a slow addition of
methanol (0.20 mL, 5.0 mmol). The mixture was stirred
for 3 h, while it was allowed to slowly warm from –100 °C
to –78 °C and it was oxidised with NaOH (3 M in H
2
O; 2
mL) and (slowly!) H
2
O
2
(30% in H
2
O; 1.2 mL) and was left
stirring under positive N
2
pressure while it slowly warmed
to RT. The product was then extracted with Et
2
O (3×50
mL), treated with HCl (20% in H
2
O; 5 mL), and stirred for
0.2 h. To the mixture was added water (50 mL) to extract
the product. After removal of the organic layer, the
aqueous solution of amine hydrochloride was neutralised
with NaOH until pH~8. The resulting amine was extracted
with Et
2
O (3×50 mL), the solvent was removed under
reduced pressure, and the material was purified on silica gel
(hexanes:ethyl acetate:triethylamine 84.5:15:0.5) to afford
0.66 g (4.5 mmol, 90% yield) of
2a
with 88% ee as
analysed by the HPLC, having identical spectral data to the
reported above. [
Å‹
]
2
D
= +39 (CHCl
3
,
c =
0.10), lit.: +42
(CHCl
3
,
c =
0.5).
NH
2
NH
2
(1
S
)-1-phenylbut-3-en-1-amine (
2a
) from
N
-
silyl imine (
1a
). To a stirring solution of (–)-
B
-
allyldiisopinocampheylborane (
I
; 1 M in pentane; 6 mL, 6
mmol) diluted with THF (5 mL) and cooled to –78 °C was
added
1a
(0.9 g, 5.1 mmol), followed by a slow addition of
water (0.09 mL, 5.0 mmol) in THF (0.5 ml). The mixture
was stirred for 1 h at –78 °C and it was oxidised with
NaOH (3 M in H
2
O; 2 mL) and (slowly!) H
2
O
2
(30% in
H
2
O; 1.2 mL) and was left stirring under positive N
2
pressure while it slowly warmed to RT. The product was
then extracted with Et
2
O (3×50 mL), treated with HCl
(30% in H
2
O; 3 mL), and stirred for 0.2 h. To the mixture
was added water (50 mL) to extract the product. After
removal of the organic layer, the aqueous solution of amine
hydrochloride was neutralised with NaOH until pH~8. The
resulting amine was extracted with Et
2
O (3×50 mL), the
solvent was removed under reduced pressure, and the
material was purified on silica gel (hexanes:ethyl
acetate:triethylamine 84.5:15:0.5) to afford 0.66 g (4.5
mmol, 90% yield) of
2a
having 92% ee (HPLC analysis
using Chiracel OD-H column and
hexanes/isopropanol/triethylamine as the mobile phase).
1
H
NMR (300 MHz, CDCl
3
,
Ō
): 1.69 (br s, 2H), 2.32-2.50 (m,
2H), 4.00 (d,
J
= 8.0 Hz, 1H), 5.07-5.15 (m, 2H), 5.69-5.82
(m, 1H), 7.22-7.37 (m, 5H);
13
C NMR (75 MHz, CDCl
3
,
Ō
):
44.2, 55.4, 117.7, 126.4, 127.0, 128.5, 135.5, 145.8. MS
(EI): 128, 106 [Ph-CH
+
-NH
2
], 79; (CI): 148 [
M
+H], 131
[
M
–NH
3
]; HRMS: 148.1126 (calc.), 148.1129 (actual).
[
Å‹
]
2
D
= +43 (CHCl
3
,
c =
1.9), lit.:
+42, CHCl
3
,
c =
0.5).
S
(1
S
)-1-thien-2-ylbut-3-en-1-amine (
2b
).
1
H NMR (200 MHz, CDCl
3
,
Ō
): 1.84 (br s, 2H), 2.35-2.75
(m, 2H), 4.29 (t,
J =
5.2 Hz, 1H), 5.10-5.19 (m, 1H), 5.68-
5.89 (m, 1H), 6.92-6.96 (m, 2H), 7.10-7.20 (m, 1H);
13
C
NMR (50 MHz, CDCl
3
,
Ō
): 45.3, 51.8, 118.2, 122.8, 123.6,
126.5, 134.5. [
Å‹
]
2
D
=
–20 (CDCl
3
,
c =
3.75).
NH
2
O
(1
S
)-1-(4-methoxyphenyl)but-3-
en-1-amine (
2c
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 1.71 (br
1
Ph
Ph
s, 2H), 2.39-2.51 (m, 2H), 3.87 (s, 3H), 4.03 (dd,
J =
7.6
Hz, 5.8 Hz, 1H), 5.13-5.22 (m, 2H), 5.75-5.89 (m, 1H),
6.95 (d,
J =
8.4 Hz, 2H), 7.33 (d,
J =
8.7 Hz, 2H);
13
C
NMR (75 MHz, CDCl
3
,
Ō
): 44.6, 55.1, 55.6, 114.1, 117.8,
126.7, 135.9, 138.3, 158.9. [
Å‹
]
2
D
=
–25 (CDCl
3
,
c =
4.90).
NH
2
NH
2
(1
S
)-1-cyclohexylbut-3-en-1-amine (
3i
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 0.94-1.30 (m, 6H), 1.37 (br
s, 2H), 1.67-1.78 (m, 5H), 1.93-2.01 (m, 1H), 2.25-2.31 (m,
1H), 2.56 (q,
J =
4.2 Hz, 1H), 5.06-5.12 (m, 2H), 5.73-5.84
(m, 1H);
13
C NMR (75 MHz, CDCl
3
,
Ō
): 26.5, 26.6, 26.7,
28.4, 29.8, 39.5, 43.5, 55.4, 117.2, 136.7. MS (EI):152 [
M
–
H], 112 [
M
–C
3
H
5
], 95, 70; (CI):154 [
M
+H], 112; HRMS:
154.1596 (calc.), 154.1599 (actual). [
Å‹
]
2
D
=
+9 (CHCl
3
,
c =
0.37).
(1
S
)-1-(4-nitrophenyl)but-3-en-1-
amine (
2f
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 1.70 (br s, 2H),
2.37-2.57 (m, 2H), 4.21 (dd,
J =
7.6 Hz, 5.2 Hz, 1H), 5.17-
5.21 (m, 2H), 5.72-5.86 (m, 1H), 7.60 (d,
J =
8.7 Hz, 2H),
8.25 (d,
J =
8.7 Hz, 2H);
13
C NMR (75 MHz, CDCl
3
,
Ō
):
44.0, 54.8, 118.6, 123.6, 127.2, 134.2, 146.9, 153.2. [
Å‹
]
2
D
=
–24 (CDCl
3
,
c =
5.65).
NH
2
NH
2
Ph
F
(1
S
,2
S
)-2-methyl-1-phenylbut-3-en-1-amine
(
5a
). To potassium
tert
-butoxide (1 M in THF; 6 mL, 6
mmol) diluted with THF (6 mL) and cooled to –78 °C was
added
trans
-butene (1 mL, 11 mmol) and butyllithium (2.5
M in hexanes; 2.4 mL, 6.0 mmol). The mixture was stirred
for 0.1 h at –78 °C, followed by 0.3 h at –55 °C, and cooled
again to –78 °C, when a solution of (–)-
B
-
methoxydiisopinocampheylborane (2.28 g, 7.2 mmol) in
THF (5 mL) was added and the reaction was stirred for 1 h
at –78 °C. To thus generated
V
was added via canula
4a
[prepared as follows: To
3a
(0.52 mL, 5.05 mmol) diluted
with THF (5 mL) and cooled to 0 ºC was added DIBAL-H
(0.89 mL, 5.0 mmol) and the mixture was stirred for 1 h],
followed by methanol (0.20 mL, 5.0 mmol) and the mixture
was stirred for 3 h at –78 °C, when it was oxidized with
NaOH (3 M in H
2
O; 2 mL) and (slowly!) H
2
O
2
(30% in
H
2
O; 1.2 mL) and was left stirring under positive N
2
pressure while it slowly warmed to RT. The product was
extracted with Et
2
O (3×50 mL) after the acid-base
manipulation, the solvent was removed under reduced
pressure, and the crude material was purified on silica gel
(hexanes:ethyl acetate:triethylamine 84.5:15:0.5) to afford
0.59 g (3.7 mmol, 74% yield) of
5a.
1
H NMR (300 MHz,
CDCl
3
,
Ō
): 0.83 (d,
J =
6.7 Hz, 3H), 1.53 (br s, 2H), 2.37
(q,
J =
7.4 Hz, 1H), 3.65 (d,
J =
8.46 Hz, 1H), 5.10-5.204
(m, 2H), 5.69-5.81 (m, 1H), 7.26-7.33 (m, 5H);
13
C NMR
(75 MHz, CDCl
3
,
Ō
): 17.7, 46.4, 60.7, 115.9, 127.1, 127.3,
128.3, 141.8, 144.7. MS (EI): 160 [
M
–H], 106, 79; (CI):
162, 145, 106. [
Å‹
]
2
D
= +76 (CHCl
3
,
c =
0.92), lit: +1.5
(MeOH,
c =
1.0).
NH
2
F
F
F
(1
S
)-1-pentafluorophenylbut-3-en-1-
amine (
2g
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 1.85 (br s, 2H),
2.48-2.65 (m, 2H), 4.32 (t,
J =
7.4 Hz, 1H), 5.03-5.09 (m,
2H), 5.64-5.73 (m, 1H);
19
F NMR (282 MHz, CDCl
3
,
Ō
): –
159.80-–160.00 (m, 2F), –154.23 (t,
J =
22.3 Hz, 1F), –
141.70 (t,
J =
12.1 Hz, 2F);
13
C NMR (75 MHz, CDCl
3
,
Ō
):
42.2, 48.0, 118.8, 134.2, 136.0-146.8 (m). MS (EI): 196
[
M
–C
3
H
5
], 99; (CI): 238 [
M
+H], 196. [
Å‹
]
2
D
=
+11 (CHCl
3
,
c =
5.57).
F
NH
2
(1
R
)-1-butylbut-3-enylamine (
2h
).
To a solution of valeronitrile (
3h
) (0.53 mL, 5.05 mmol) in
Et
2
O (5 mL) cooled to 0 ºC was added DIBAL-H (0.89 mL,
5.0 mmol) and the mixture was stirred for 1 h. The
obtained aluminoimine (
4h
) was transferred
via
canula to a
solution of (–)-
B
-allyldiisopinocampheylborane (1 M in
pentane; 8 mL, 8 mmol) diluted with Et
2
O (8 mL) and
cooled to –55 °C, followed by slow addition of methanol
(0.20 mL, 5.0 mmol). The mixture was stirred for 3 h at –
55 °C, followed by oxidation with NaOH (3 M in H
2
O; 2
mL) and (slowly!) H
2
O
2
(30% in H
2
O; 1.2 mL) and was left
stirring under positive N
2
pressure while it slowly warmed
to RT. The product was then extracted with Et
2
O (3×50
mL), treated with HCl (20% in H
2
O, 5 mL), and stirred for
0.2 h. To the mixture was added water (50 mL) to extract
the product. After removal of the organic layer, the
aqueous solution of amine hydrochloride was neutralised
with NaOH until pH~8. The resulting amine was extracted
with Et
2
O (3×50 mL), the solvent was removed under
reduced pressure, and the material was purified on silica gel
(hexanes:ethyl acetate:triethylamine 84.5:15:0.5) to afford
0.4 g (3.1 mmol, 65% yield) of
2h
.
1
H NMR (200 MHz,
CDCl
3
,
Ō
): 0.95 (m, 3H), 1.30-1.48 (m, 8H), 1.87-2.02 (m,
1H), 2.18-2.24 (m, 1H), 2.07-2.08 (m, 1H), 5.01-5.07 (m,
2H), 5.66-5.82 (m, 1H);
13
C NMR (50 MHz, CDCl
3
,
Ō
):
15.0, 23.6, 29.2, 38.0, 43.2, 51.1, 117.2, 135.7. MS
(EI):126 [
M
+
], 86 [
M
–C
3
H
5
], 70; (CI):154 [
M
+H], 136
[
M
+
], 70. [
Å‹
]
2
D
=
+4 (CDCl
3
,
c =
2.75).
S
(1
S
,2
S
)-2-methyl-1-thien-2-ylbut-3-en-
1-amine (
5b
).
1
H NMR (200 MHz, CDCl
3
,
Ō
): 0.92 (d,
J =
6.8 Hz, 3H), 1.71 (br s, 2H), 2.38 (q,
J =
7.3 Hz, 1H), 3.98
(d,
J =
7.8 Hz, 1H), 5.03-5.21 (m, 2H), 5.45.816 (m 1H),
6.90-6.94 (m, 2H), 7.17-7.20 (m, 1H);
13
C NMR (50 MHz,
CDCl
3
,
Ō
): 18.2, 47.5, 56.9, 116.3, 123.7, 123.8, 126.0,
140.7, 148.8. [
Å‹
]
2
D
=
+6 (CHCl
3
,
c =
1.55).
2
O
2
N
NH
2
NH
2
(1
R
,2
S
)-1-butyl-2-methylbut-3-
enylamine (
5h
). To potassium
tert
-butoxide (1 M in THF; 6
mL, 6 mmol) diluted with pentane (6 mL) and cooled to –
78 °C was added
trans
-butene (1 mL, 11 mmol) and
butyllithium (2.5 M in hexanes; 2.4 mL, 6.0 mmol). The
mixture was stirred for 0.1 h at –78 °C, followed by 0.3 h at
–55 °C, and cooled again to –78 °C, when a solution of (–)-
B
-methoxydiisopinocampheylborane (2.28 g, 7.2 mmol) in
pentane (5 mL) was added and the reaction was stirred for
1 h at –78 °C. To thus generated
V
was added via canula a
solution of
4h
[prepared as follows: To a solution of
valeronitrile (
3h
) (0.55 mL, 5.2 mmol) in pentane (10 mL)
cooled to 0 ºC was added DIBAL-H (0.90 mL, 5.0 mmol)
and the mixture was stirred for 1 h], followed by methanol
(0.20 mL, 5.0 mmol) and the mixture was stirred for 3 h at
–78 °C when it was oxidised with NaOH (3 M in H
2
O; 2
mL) and (slowly!) H
2
O
2
(30% in H
2
O; 1.2 mL) and was left
stirring under positive N
2
pressure while it slowly warmed
to RT. The product was extracted with Et
2
O (3×50 mL)
after the acid-base manipulations, the solvent was removed
under reduced pressure, and the crude material was purified
on silica gel (hexanes:ethyl acetate:triethylamine
84.5:15:0.5) to afford 0.4 g (2.8 mmol, 64% yield) of
5h.
1
H NMR (200 MHz, CDCl
3
,
Ō
): 0.95 (t,
J =
4.5 Hz, 3H),
1.06 (d,
J =
4.6 Hz, 3H), 1.27-1.40 (m, 8H), 2.16 (q,
J =
4.5 Hz, 1H), 2.57-2.60 (m, 1H), 5.06-5.09 (m, 2H), 5.72-
5.84 (m, 1H);
13
C NMR (50 MHz, CDCl
3
,
Ō
): 14.4, 17.0,
23.2, 28.9, 34.9, 44.3, 55.6, 115.4, 141.4. MS (EI): 142
[
M
+H], 86 [
M
–C
4
H
7
]; (CI): 142 [
M
+H], 86. [
Å‹
]
2
D
= +15
(CDCl
3
,
c =
1.28).
NH
2
S
(1
S
,2
R
)-2-methyl-1-thien-2-ylbut-3-en-1-
amine (
6b
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 1.03 (d,
J =
6.5 Hz, 3H), 1.64 (br s, 2H), 2.56 (q,
J =
6.4 Hz, 1H), 4.19
(d,
J =
4.9 Hz, 1H), 5.05-5.08 (m, 2H), 5.73-5.79 (m, 1H),
6.89-6.93 (m, 2H), 7.20 (dd,
J =
8.2 Hz, 12.1 Hz, 1H);
13
C
NMR (75 MHz, CDCl
3
,
Ō
): 14.9, 44.9, 56.1, 115.7, 123.6,
123.6, 126.4, 140.4, 149.1. MS (EI): 150, 112, 85; (CI):
168 (
M
+H], 151[
M
+H–NH
3
], 112. HRMS: 168.0847
(calc.), 168.0852 (actual). [
Å‹
]
2
D
=
–53 (CDCl
3
,
c =
2.46).
NH
2
(1
R
,2
R
)-1-butyl-2-methylbut-3-
enylamine (
6h
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 0.96 (t,
J
=
6.7 Hz, 3H), 1.03 (d,
J =
6.6 Hz, 3H), 1.24-1.52 (m, 8H),
2.23 (q,
J =
6.0 Hz, 1H), 2.68-2.71 (m, 1H), 5.05-5.12 (m,
2H), 5.77-5.88 (m, 1H);
13
C NMR (75 MHz, CDCl
3
,
Ō
):
14.3, 14.4, 23.1, 29.2, 34.6, 43.7, 55.4, 114.7, 142.4. MS
(EI): 142 [
M
+H], 86 [
M
–C
4
H
7
], 69, 44; (CI): 142 [
M
+H],
86. [
Å‹
]
2
D
=
+25 (CDCl
3
,
c =
5.25).
NH
2
(1
R
,2
R
)-1-cyclohexyl-2-methylbut-3-
en-1-amine (
6i
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 1.03 (d,
J
=
6.6 Hz, 3H), 1.16-1.43 (m, 7H), 1.68-1.92 (m, 6H), 2.37-
2.42 (m, 2H), 5.05-5.11 (m, 2H), 5.78-5.90 (m, 1H);
13
C
NMR (75 MHz, CDCl
3
,
Ō
): 13.5, 26.6, 26.8, 26.9, 28.5,
30.8, 40.0, 41.0, 60.0, 114.2, 143.5. [
Å‹
]
2
D
=
+70 (CDCl
3
,
c
=
1.66).
NH
2
Ph
(1
R
,2
S
)-1-cyclohexyl-2-methylbut-3-en-
1-amine (
5i
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 0.99 (d,
J =
6.4 Hz, 3H), 1.05-1.20 (m, 8H), 1.60-1.68 (m, 5H), 2.24-
2.26 (m, 2H), 4,.99-5.06 (m, 2H), 5.66-5.72 (m, 1H);
13
C
NMR (75 MHz, CDCl
3
,
Ō
): 18.0, 26.7, 26.9, 27.0, 27.4,
31.2, 40.7, 41.1, 60.3, 115.4, 141.8. MS (EI): 169 [
M
+H],
150 [
M
–NH
3
], 112 [
M
–C
4
H
7
]; (CI): 168 [
M
+H], 151, 112;
HRMS: 168.1752 (calc.), 168.1757 (actual). [
Å‹
]
2
D
=
–18
(CDCl
3
,
c =
5.80).
NH
2
O O
O
(1
R
,2
R
)-2-[(2-
Methoxyethoxy)methoxy]-1-phenylbut-3-en-1-amine (
7a
).
To 3-[(2-methoxyethoxy)-methoxy]prop-1-ene (0.91 g, 6.2
mmol) diluted with THF (6 mL) and cooled to –78 °C was
added
sec
-butyllithium (1.4 M in cyclohexane; 4.4 mL, 6.1
mmol) and the mixture was stirred for 0.5 h at –78 °C.
Then, a solution of (–)-
B
-
methoxydiisopinocampheylborane (2.37 g, 7.5 mmol) in
THF (5 mL) was added and the mixture was stirred for 1 h.
To thus generated
VII
was added via canula a solution of
4a
[prepared as follows: To
3a
(0.52 mL, 5.05 mmol)
diluted with THF (5 mL) and cooled to 0 ºC was added
DIBAL-H (0.89 mL, 5.0 mmol) and the mixture was stirred
for 1 h], followed by methanol (0.20 mL, 5.0 mmol). The
reaction was stirred for 3 h at –78 °C and was oxidised with
NaOH (3 M in H
2
O; 2 mL) and (slowly!) H
2
O
2
(30% in
H
2
O; 1.2 mL). The material was left stirring under positive
N
2
pressure while it slowly warmed to RT. The product
was extracted with Et
2
O (3×50 mL) and the volatiles were
removed under reduced pressure. The obtained material
was purified on silica gel (hexanes:ethyl
acetate:triethylamine 94.5:5:0.5 to 69.5:30:0.5) to furnish
Ph
(1
S
,2
R
)-2-methyl-1-phenylbut-3-en-1-amine
(
6a
). Amines
6
were obtained like
5
, however
cis
-butene
was used in place of
trans
-butene.
1
H NMR (300 MHz,
CDCl
3
,
Ō
): 1.06 (d,
J =
7.2 Hz, 3H), 1.65 (br s, 2H), 2.57
(q,
J =
8.6 Hz, 1H), 3.96 (d,
J =
5.1 Hz, 1H), 5.08-5.11 (m,
2H), 5.70-5.76 (m, 1H), 7.28-7.36 (m, 5H);
13
C NMR (75
MHz, CDCl
3
,
Ō
): 15.3, 45.0, 60.2, 115.3, 127.1, 127.4,
128.3, 141.3, 144.5. [
Å‹
]
2
D
=
–27 (CDCl
3
,
c =
2.46).
3
7a
in 65% yield (0.81 g, 3.2 mmol).
1
H NMR (300 MHz,
CDCl
3
,
Ō
): 1.73 (br s, 2H), 3.34 (s, 3H), 3.37-3.49 (m, 4H),
3.96 (d,
J =
5.8 Hz, 1H), 4.18 (t,
J =
6.5 Hz, 1H), 4.67 (dd,
J =
6.9 Hz, 38.7 Hz, 2H), 5.11-5.11 (m, 2H), 5.58-5.69 (m,
1H), 7.21-7.34 (m, 5H);
13
C NMR (75 MHz, CDCl
3
,
Ō
):
59.0, 59.8, 67.0, 71.7, 81.7, 93.0, 118.7, 127.2, 127.5,
128.2, 135.5, 142.6. MS (EI):176 [
M
–OCH
2
CH
2
OCH
3
],
106, 79, 59; (CI):252 [
M
+H], 176 [
M
+H–
CH
3
OCH
2
CH
2
OH], 106, 79; HRMS: 252.1600 (calc.),
252.1604 (actual). [
Å‹
]
2
D
= +103 (CHCl
3
,
c =
4.22).
NH
2
1. Boc
2
O
2. O
3
/ Me
2
S
3. NaClO
2
4. HCl
(3
S
)-3-
Amino-3-phenylpropanoic acid hydrochloride (
8a
). To
2a
(0.43 g, 2.9 mmol) dissolved in Et
2
O (30 mL) was added
di-
tert
-butyldicarbonate (0.7 g, 3.55 mmol) and the reaction
was stirred for 6 h at RT, after which time the solvent was
removed under reduced pressure. The crude material was
dissolved in CH
2
Cl
2
(150 mL) and methanol (150 mL) and
cooled to –78 ºC. Ozone was passed for 1 h (aqueous KI
used as an indicator), followed by quenching with Me
2
S (2
mL) at –78 °C and stirring for 1 h, while the material
warmed to RT. The mixture was washed with H
2
O (50
mL) and the organic layer was concentrated under reduced
pressure. The crude aldehyde was diluted with 2-
methylpropan-2-ol (30 mL) and 2-methylbut-2-ene (5 mL)
and to this were added sodium chlorite (2.2 g, 24.3 mmol),
sodium phosphate monobasic (2.3 g, 16.9 mmol), and water
(6 mL). The mixture was stirred at RT for 1 h and the
product was extracted with ethyl acetate (3×60 mL). The
solvents were removed under reduced pressure and the
obtained acid was filtered through a short plug of silica gel
(ether). After evaporation of the solvent, the residue was
diluted with Et
2
O (10 mL) and treated with HCl (1 M in
Et
2
O; 3 mL, 3 mmol) for 0.5 h. The obtained solid was
filtered and dried to afford
8a
in 84% yield (0.49 g, 2.4
mmol).
1
H NMR (200 MHz, D
2
O,
Ō
): 2.93-3.01 (m, 2H),
4.57 (t,
J =
7.2 Hz, 1H), 7.24-7.31 (m, 5H);
13
C NMR (50
MHz, D
2
O, d): 38.7, 52.4, 127.2, 129.6, 129.8, 135.2,
173.2. [
Å‹
]
2
D
=
+6 (D
2
O,
c =
0.9), +3.9 (MeOH,
c =
0.8),
(lit.: +3, MeOH,
c =
2.9).
NH
2
NH
2
OH
HCl
Ph
Ph
O
S
O
O
O
(1
S
,2
R
)-2-[(2-
Methoxyethoxy)methoxy]-1-thien-2-ylbut-3-en-1-amine
(
7b
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 2.06 (br s, 2H), 3.36
(s, 3H), 3.45-3.63 (m, 4H), 4.18 (t,
J =
6.6 Hz, 1H), 4.26
(d,
J =
5.8 Hz, 1H), 4.72 (dd,
J =
6.9 Hz, 34.5 Hz, 2H),
5.11-5.24 (m, 2H), 5.61-5.73 (m, 1H), 6.86-6.94 (m, 2H),
7.19 (dd,
J =
1.4 Hz, 4.7 Hz, 1H);
13
C NMR (75 MHz,
CDCl
3
,
Ō
): 55.8, 59.0, 67.2, 71.7, 81.9, 93.1, 119.4, 124.2,
124.3, 126.4, 135.0, 146.8. MS (EI):205, 112 [2-Thp-
CH
+
NH
2
], 85, 59; (CI): 258 [
M
+H], 182, 165, 112, 89
[CH
3
OCH
2
CH
2
OCH
2
+
]; HRMS: 258.1164 (calc.), 258.1166
(actual). [
Å‹
]
2
D
=
+73 (CHCl
3
,
c =
9.08).
NH
2
O O
O
(1
R
,2
R
)-1-Butyl-2-[(2-
methoxyethoxy)methoxy]but-3-enylamine (
7h
).
1
H NMR
(300 MHz, CDCl
3
,
Ō
): 0.86 (t,
J =
6.8 Hz, 3H), 1.23-1.45
(m, 5H), 2.65-2.69 (m, 1H), 3.34 (s, 3H), 3.49-3.60 (m,
3H), 3.76-3.83 (m, 2H), 4.69 (dd,
J =
6.9 Hz, 33.9 Hz, 2H),
5.18-5.26 (m, 2H), 5.58-5.70 (m, 1H);
13
C NMR (75 MHz,
CDCl
3
,
Ō
): 14.1, 22.8, 28.4, 33.2, 54.7, 59.0, 67.2, 71.7,
81.6, 92.9, 119.1, 135.9. MS (EI): 156 [
M
–
OCH
2
CH
2
OCH
3
], 86 [CH
3
CH
2
CH
2
CH
2
CH
+
NH
2
], 232 [self-
protonating in EI]; (CI): 232 [
M
+H], 156 [
M
+H–
HOCH
2
CH
2
OCH
3
], 126, 86; HRMS: 232.1913 (calc.),
232.1913 (actual). [
Å‹
]
2
D
=
+70 (CHCl
3
,
c =
2.25).
NH
2
F
NH
2
OH
HCl
F
O
F
F
(3
S
)-3-Amino-3-
pentafluorophenylpropanoic acid hydrochloride (
8g
).
1
H
NMR (300 MHz, D
2
O,
Ō
): 3.06-3.30 (m, 2H), 5.15 (t,
J =
6.9 Hz, 1H);
19
F NMR (282 MHz, D
2
O, d): –161.09-–
160.90 (m, 2F), –151.41 (t,
J =
20.7 Hz, 1F), –141.62-–
141.54 (m, 2F);
13
C NMR (75 MHz, D
2
O,
Ō
): 35.8, 42.0,
172.1. [
Å‹
]
2
D
=
+24 (D
2
O,
c =
2.47).
F
O O
O
(1
R
,2
R
)-1-Cyclohexyl-2-[(2-
methoxyethoxy)methoxy]but-3-en-1-amine (
7i
).
1
H NMR
(300 MHz, CDCl
3
,
Ō
): 1.07-1.34 (m, 9H), 1.67-1.76 (m,
5H), 2.47 (t,
J =
5.2 Hz, 1H), 3.38 (s, 3H), 3.53-3.63 (m,
3H), 3.80-3.86 (m, 1H), 4.07 (t,
J =
6.6 Hz, 1H), 4.72 (dd,
J =
7.0 Hz, 36.3 Hz, 2H), 5.22-5.29 (m, 2H), 5.65-5.76 (m,
1H);
13
C NMR (75 MHz, CDCl
3
,
Ō
): 25.3, 25.5, 25.6, 26.4,
28.7, 29.7, 38.6, 58.0, 58.6, 66.3, 70.7, 78.1, 91.9, 117.5.
MS (EI): 205, 112, 95, 59; (CI): 258 (
M
+H], 182, 112;
HRMS: 258.2069 (calc.), 258.2073 (actual). [
Å‹
]
2
D
=
+18
(CHCl
3
,
c =
0.25).
NH
2
OH
HCl
(3
S
)-3-Aminoheptanoic acid
hydrochloride (
8h
).
1
H NMR (200 MHz, D
2
O,
Ō
): 0.82 (t,
J
=
4.8 Hz, 3H), 1.29-1.12 (m, 6H), 1.60-1.64 (m, 2H), 2.59-
2.82 (m, 2H), 3.51-3.61 (m, 1H);
13
C NMR (50 MHz, D
2
O,
Ō
): 14.2, 22.7, 27.6, 32.6, 36.8, 49.1, 174.1. [
Å‹
]
2
D
=
+39
(D
2
O,
c =
4.39).
O
1. Boc
2
O
2. NaIO4 / RuCl
3
(cat)
3. HCl
NH
2
NH
2
OH
HCl
Ph
Ph
O
(2
R
,3
S
)-3-Amino-2-methyl-3-phenylpropanoic acid
hydrochloride (
8a'
). To
6a
(0.2 g, 1.2 mol) dissolved in
Et
2
O (12 mL) was added di-
tert
-butyldicarbonate (0.3 g,
4
1.4 mmol) and the reaction was stirred for 6 h at RT, after
which time the solvent was removed under reduced
pressure. To the crude material dissolved in CH
3
CN (40
mL) was added RuCl
3
·H
2
O (0.02 g, 0.1 mmol) and the
mixture was cooled to 0 °C. After addition of NaIO
4
(0.8
g, 3.7 mmol) dissolved in water (40 mL), the mixture was
stirred for 0.5 h, followed by extraction with EtOAc (3×30
mL) and filtration through silica gel (Et
2
O). After
evaporation of the solvents, the residue was diluted with
Et
2
O (5 mL) and treated with HCl (1 M in Et
2
O; 2 mL, 2
mmol) for 0.5 h. The obtained solid was filtered and dried
to afford
8a'
in 77% yield (0.2 g, 0.9 mmol).
1
H NMR (200
MHz, D
2
O,
Ō
): 0.91 (d,
J =
7.2 Hz, 3H), 2.97-3.09 (m, 1H),
4.36 (d,
J =
9.4 Hz, 1H), 7.29-7.31 (m, 5H);
13
C NMR (50
MHz, D
2
O,
Ō
):15.4, 43.9, 57.8, 127.4, 127.6, 129.6, 129.8,
134.5, 177.3. [
Å‹
]
2
D
= +19 (D
2
O,
c =
1.19).
4.73 (br s, 1H), 5.10 (br s, 1H), 7.28-7.36 (m, 5H);
13
C
NMR (75 MHz, CDCl
3
,
Ō
): 14.9, 28.3, 35.4, 36.3, 58.2,
60.7, 79.5, 126.5, 126.8, 128.3, 141.8, 155.7.
NHBoc
Ph
OH
OMEM
tert
-butyl (1
R
,2
R
)-[4-hydroxy-2-(2-
methoxy-ethoxymethoxy)-1-phenylbutyl]-carbamate (
9a"
).
To
7a
(0.3 g, 1.2 mmol) dissolved in Et
2
O (12 mL) was
added di-
tert
-butyldicarbonate (0.4 g, 1.3 mmol) and the
reaction was stirred for 3 h at RT, after which time the
solvent was removed under reduced pressure. The crude
material dissolved in THF (6 mL) was added to a slurry of
dicyclohexylborane (0.5 g, 2.8 mmol) in THF (6 mL) and
stirred for 16 h at RT, cooled to 0 °C and oxidised with
NaOH (3 M in H
2
O, 0.4 mL) and (slowly!) H
2
O
2
(30% in
H
2
O; 0.7 mL) for 3 h at RT. The product was extracted
with Et
2
O (3×30 mL), washed with brine, and after
evaporation of the solvents purified on silica gel (flash;
hexanes:ethyl acetate 1:1) to furnish the desired primary
alcohol
9a"
in 68% yield (0.2 g, 0.7 mmol).
1
H NMR (200
MHz, CDCl
3
,
Ō
): 1.41 (s, 9H), 1.70-1.90 (m, 2H), 2.75 (br
s, 1H), 3.32 (s, 3H), 3.37-3.41 (m, 3H), 3.56-3.77 (m, 3H),
4.06-4.14 (m, 2H), 4.48 (d,
J =
6.8 Hz, 1H), 4.76 (d,
J =
7.0 Hz, 1H), 5.51 (d,
J =
7.8 Hz, 1H), 7.19-7.26 (m, 5H);
13
C NMR (50 MHz, CDCl
3
, d): 29.1, 35.9, 57.7, 58.9, 59.4,
67.7, 71.9, 79.0, 79.8, 95.8, 126.2, 127.0, 128.2, 140.8,
155.3.
NH
2
OH
HCl
Ph
O
OH
(2
S
,3
R
)-3-Amino-2-hydroxy-3-
phenylpropanoic acid hydrochloride (
8a"
):
1
H NMR (200
MHz, CD
3
OD,
Ō
): 3.24-3.29 (m, 1H), 3.86 (t,
J =
4.5 Hz,
1H), 4.51 (d,
J =
3.6 Hz, 1H), 7.36-7.40 (m, 5H); [
Å‹
]
2
D
=
+17 (D
2
O,
c =
0.8).
NHBoc
tert
-butyl (1
S
)-4-hydroxy-1-
phenylbutylcarbamate (
9a
). To
2a
(0.43 g, 2.9 mmol)
dissolved in Et
2
O (30 mL) was added di-
tert
-
butyldicarbonate (0.7 g, 3.5 mmol) and the reaction was
stirred for 6 h at RT, after which time the solvent was
removed under reduced pressure. The crude material was
dissolved in THF (7 mL) and treated with 9-BBN (0.5 M in
THF; 13 mL, 6.5 mmol) for 24 h at RT, followed by
oxidation with NaOAc (20% in H
2
O, 20 mL) and H
2
O
2
(30% in H
2
O; 6 mL) for 3 h at RT. The product was
extracted with Et
2
O (3×30 mL), washed with brine, and
after evaporation of the solvents purified on silica gel
(flash; hexanes:ethyl acetate 2:1) to furnish
9a
in 86% yield
(0.66 g, 2.5 mmol).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 1.45
(s, 9H), 1.53-1.88 (m, 4H), 2.55 (br s, 1H), 3.67 (t,
J =
5.9
Hz, 2H), 4.67 (br s, 1H), 5.12 (br s, 1H), 7.29-7.39 (m, 5H);
13
C NMR (75 MHz, CDCl
3
,
Ō
): 28.3, 29.1, 33.2, 54.6, 62.1,
79.5, 126.3, 127.2, 128.5, 142.7, 155.5.
NHBoc
OH
NHBoc
Ph
OH
O
(4
S
)-4-[(
tert
-butoxycarbonyl)amino]-4-
phenylbutanoic acid (
10a
). The alcohol
9a
(0.22 g, 0.8
mmol) in DMF (10 mL) was added slowly to a stirring
solution of pyridinium dichromate (1.13 g, 3.0 mmol) in
DMF (20 mL) and the mixture was stirred for 18 h at RT.
The reaction was quenched with H
2
O (5 mL), the product
was extracted with Et
2
O (3×50 mL), the combined ether
layers were washed with H
2
O (3×50 mL), the solvent was
removed and the obtained material was purified on silica
gel (flash; hexanes:ethyl acetate 2:1) to afford 0.192 g (0.7
mmol, 86% yield) of
10a
.
1
H NMR (200 MHz, CDCl
3
,
Ō
):
1.22 (s, 9H), 1.78-2.01 (m, 1H), 2.35-2.71 (m, 3H), 5.07-
5.13 (m, 1H), 7.15-7.34 (m, 5H);
13
C NMR (50 MHz,
CDCl
3
,
Ō
): 28.0, 28.3, 31.9, 61.9, 82.9, 124.8, 127.3, 128.4,
142.1, 149.0, 174.1.
NHBoc
OH
tert
-butyl (1
R
)-1-(3-
hydroxypropyl)pentylcarbamate (
9h
).
1
H NMR (300 MHz,
CDCl
3
,
Ō
): 0.93 (d,
J =
6.3 Hz, 3H), 1.47 (s, 10H), 1.65-
1.69 (m, 1H), 2.12 (br s, 1H), 2.45 (br s, 1H), 3.70-3.76 (m,
2H), 4.73 (br s, 1H), 5.10 (br s, 1H), 7.28-7.36 (m, 5H);
13
C
NMR (75 MHz, CDCl
3
,
Ō
): 14.9, 28.3, 35.4, 36.3, 58.2,
60.7, 79.5, 126.5, 126.8, 128.3, 141.8, 155.7.
OH
NHBoc
O
(4
R
)-4-[(
tert
-
butoxycarbonyl)amino]octanoic acid (
10h
).
1
H NMR (200
MHz, CDCl
3
,
Ō
): 0.91 (t,
J =
6.6 Hz, 3H), 1.20-2.67 (m,
11H), 4.04-4.12 (m, 1H);
13
C NMR (50 MHz, CDCl
3
, d):
14.9, 23.2, 28.5, 28.8, 32.1, 34.0, 58.5, 82.9, 149.6, 174.0.
OH
Ph
NHBoc
tert
-butyl (1
S
,2
R
)-4-hydroxy-2-methyl-
1-phenylbutylcarbamate (
9a'
).
1
H NMR (300 MHz, CDCl
3
,
Ō
): 0.93 (d,
J =
6.3 Hz, 3H), 1.47 (s, 10H), 1.65-1.69 (m,
1H), 2.12 (br s, 1H), 2.45 (br s, 1H), 3.70-3.76 (m, 2H),
Ph
OH
O
(3
R
,4
S
)-4-[(
tert
-
butoxycarbonyl)amino]-3-methyl-4-phenylbutanoic acid
5
Ph
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